{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T14:46:57Z","timestamp":1771512417417,"version":"3.50.1"},"reference-count":48,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2015,7,1]],"date-time":"2015-07-01T00:00:00Z","timestamp":1435708800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,7]]},"abstract":"ABSTRACT<\/jats:title>\n \n Although amphotericin B-azole combination therapy has traditionally been questioned due to potential antagonistic interactions, it is often used successfully to treat refractory invasive aspergillosis. So far, pharmacodynamic (PD) interactions have been assessed with conventional\n in vitro<\/jats:italic>\n tests, which do not mimic human serum concentrations and animal models using limited doses. We therefore simulated the human serum concentration profiles of amphotericin B and voriconazole in an\n in vitro<\/jats:italic>\n dialysis\/diffusion closed pharmacokinetic-pharmacodynamic (PK-PD) model and studied the pharmacodynamic interactions against an azole-resistant and an azole-susceptible\n Aspergillus fumigatus<\/jats:named-content>\n isolate, using Bliss independence and canonical mixture response surface analyses. Amphotericin B dosing regimens with the drug administered every 24 h (q24h) were combined with voriconazole q12h dosing regimens.\n In vitro<\/jats:italic>\n PK-PD combination data were then combined with human PK data by using Monte Carlo analysis. The target attainment rate and the serum concentration\/MIC ratio were calculated for isolates with different MICs. Synergy (20 to 31%) was observed at low amphotericin B-high voriconazole exposures, whereas antagonism (\u22126 to \u221216%) was found at high amphotericin B-low voriconazole exposures for both isolates. Combination therapy resulted in 17 to 48% higher target attainment rates than those of monotherapy regimens for isolates with voriconazole\/amphotericin B MICs of 1 to 4 mg\/liter. Optimal activity was found for combination regimens with a 1.1 total minimum concentration of drug in serum (\n tC<\/jats:italic>\n min<\/jats:sub>\n )\/MIC ratio for voriconazole and a 0.5 total maximum concentration of drug in serum (\n tC<\/jats:italic>\n max<\/jats:sub>\n )\/MIC ratio for amphotericin B, whereas the equally effective monotherapy regimens required a voriconazole\n tC<\/jats:italic>\n min<\/jats:sub>\n \/MIC ratio of 1.8 and an amphotericin B\n tC<\/jats:italic>\n max<\/jats:sub>\n \/MIC ratio of 2.8. Amphotericin B-voriconazole combination regimens were more effective than monotherapy regimens. Therapeutic drug monitoring can be employed to optimize antifungal combination therapy with low-dose (\u22640.6 mg\/kg) amphotericin B-based combination regimens against resistant isolates for minimal toxicity.\n <\/jats:p>","DOI":"10.1128\/aac.05035-14","type":"journal-article","created":{"date-parts":[[2015,4,21]],"date-time":"2015-04-21T02:31:49Z","timestamp":1429583509000},"page":"3973-3983","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":21,"title":["Optimization of Polyene-Azole Combination Therapy against Aspergillosis Using an\n In Vitro<\/i>\n Pharmacokinetic-Pharmacodynamic Model"],"prefix":"10.1128","volume":"59","author":[{"given":"Maria","family":"Siopi","sequence":"first","affiliation":[{"name":"Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikolaos","family":"Siafakas","sequence":"additional","affiliation":[{"name":"Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophia","family":"Vourli","sequence":"additional","affiliation":[{"name":"Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loukia","family":"Zerva","sequence":"additional","affiliation":[{"name":"Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Meletiadis","sequence":"additional","affiliation":[{"name":"Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2012.08.003"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.2174\/13816128113199990330"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2006.03.016"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11908-008-0076-x"},{"key":"e_1_3_1_6_2","first-page":"24","article-title":"Combination antifungal therapy: where are we now, and where are we going?","volume":"18","author":"Marr K","year":"2004","unstructured":"Marr K. 2004. 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