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The most commonly employed combination for this infection includes a mold-active triazole and echinocandin. Few studies have evaluated combination therapy from a pharmacodynamic (PD) perspective, and even fewer have examined combination therapy against both wild-type and azole-resistant<jats:italic>Cyp51<\/jats:italic>mutant isolates. The current studies aim to fill this gap in knowledge. Four<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Aspergillus fumigatus<\/jats:named-content>isolates were utilized, including a wild-type strain, an<jats:italic>Fks1<\/jats:italic>mutant (posaconazole susceptible and caspofungin resistant), and two<jats:italic>Cyp51<\/jats:italic>mutants (posaconazole resistant). A neutropenic murine model of IPA was used for the treatment studies. The dosing design included monotherapy with posaconazole, monotherapy with caspofungin, and combination therapy with both. Efficacy was determined using quantitative PCR, and results were normalized to known quantities of conidia (conidial equivalents [CE]). The static dose, 1-log kill dose, and associated PD target area under the curve (AUC)\/MIC ratio were determined for monotherapy and combination therapy. Monotherapy experiments revealed potent activity for posaconazole, with reductions of 3 to 4 log<jats:sub>10<\/jats:sub><jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Aspergillus<\/jats:named-content>CE\/ml with the two \u201clow\u201d-MIC isolates. Posaconazole alone was less effective for the two isolates with higher MICs. Caspofungin monotherapy did not produce a significant decrease in fungal burden for any strain. Combination therapy with the two antifungals did not enhance efficacy for the two posaconazole-susceptible isolates. However, the drug combination produced synergistic activity against both posaconazole-resistant isolates. Specifically, the combination resulted in a 1- to 2-log<jats:sub>10<\/jats:sub>decline in burden that would not have been predicted based on the monotherapy results for each drug. This corresponded to a reduction in the free-drug posaconazole AUC\/MIC ratio needed for stasis of up to 17-fold. The data suggest that combination therapy using a triazole and an echinocandin may be a beneficial treatment strategy for triazole-resistant isolates.<\/jats:p>","DOI":"10.1128\/aac.00833-13","type":"journal-article","created":{"date-parts":[[2013,8,20]],"date-time":"2013-08-20T01:58:37Z","timestamp":1376963917000},"page":"5438-5447","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":29,"title":["Impact of<i>In Vivo<\/i>Triazole and Echinocandin Combination Therapy for Invasive Pulmonary Aspergillosis: Enhanced Efficacy against<i>Cyp51<\/i>Mutant Isolates"],"prefix":"10.1128","volume":"57","author":[{"given":"Alexander J.","family":"Lepak","sequence":"first","affiliation":[{"name":"University of Wisconsin, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Marchillo","sequence":"additional","affiliation":[{"name":"University of Wisconsin, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"VanHecker","sequence":"additional","affiliation":[{"name":"University of Wisconsin, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Andes","sequence":"additional","affiliation":[{"name":"University of Wisconsin, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/651263"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/651262"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1086\/652768"},{"key":"e_1_3_2_5_2","volume-title":"Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents","author":"Panel on Antiretroviral Guidelines for Adults and Adolescents","year":"2012","unstructured":"Panel on Antiretroviral Guidelines for Adults and Adolescents. 22 November 2012, accession date. 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