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As antifungal combinations are of interest to extend the spectrum of coverage and improve antifungal activity, we investigated the pharmacodynamics of olorofim in combination with posaconazole.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using galactomannan as a pharmacodynamic endpoint, olorofim and posaconazole were assessed alone and in combination in a neutropenic murine model of pulmonary aspergillosis using wild-type and triazole-resistant strains of A. fumigatus. Pharmacokinetic and pharmacodynamic data were fitted to a pharmacodynamic interaction model. Monte Carlo simulations of human-like regimens of both agents alone and in combination were performed to extrapolate to clinical settings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>With the triazole-susceptible isolate, both monotherapy arms suppressed galactomannan, but suppression with the combination was less than expected from the monotherapy arms. With the triazole-resistant isolate, monotherapy produced galactomannan suppression with olorofim but not posaconazole; the combination arm produced less suppression than olorofim alone. The interaction model revealed antagonistic pharmacodynamic interaction parameter values. Extrapolations to human pharmacokinetics predicted that combination therapy would still have a net beneficial effect in A. fumigatus infections, albeit with reduced efficacy in infections with triazole-resistant isolates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Posaconazole reduces the effect of olorofim in vivo. A combination of olorofim and a mould-active triazole is likely efficacious in wild-type infections but may be suboptimal in triazole resistance infections where there is minimal contribution of the mould-active triazole to antifungal activity and the triazole antagonises olorofim to produce a submaximal effect.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jac\/dkaf355","type":"journal-article","created":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T11:47:49Z","timestamp":1757159269000},"page":"3150-3159","source":"Crossref","is-referenced-by-count":8,"title":["Antagonistic interaction between posaconazole and olorofim in a murine model of invasive pulmonary aspergillosis"],"prefix":"10.1093","volume":"80","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5400-3413","authenticated-orcid":false,"given":"Christopher A","family":"Darlow","sequence":"first","affiliation":[{"name":"Antimicrobial Therapeutics and Pharmacodynamics, University of Liverpool , Liverpool 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