{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T21:55:12Z","timestamp":1783029312949,"version":"3.54.6"},"reference-count":30,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2000,9,1]],"date-time":"2000-09-01T00:00:00Z","timestamp":967766400000},"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":[[2000,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The interaction of amphotericin B (AmB) and azole antifungal agents in the treatment of fungal infections is still a controversial issue. A checkerboard titration broth microdilution-based method that adhered to the recommendations of the National Committee for Clinical Laboratory Standards was applied to study the in vitro interactions of AmB with fluconazole (FLC), itraconazole (ITC), and the new investigational triazole SCH 56592 (SCH) against 15 clinical isolates of\n            <jats:italic>Cryptococcus neoformans<\/jats:italic>\n            . Synergy, defined as a fractional inhibitory concentration (FIC) index of \u22640.50, was observed for 7% of the isolates in studies of the interactions of both FLC-AmB and ITC-AmB and for 33% of the isolates in studies of the SCH-AmB interactions; additivism (FICs, &gt;0.50 to 1.0) was observed for 67, 73, and 53% of the isolates in studies of the FLC-AmB, ITC-AmB, and SCH-AmB interactions, respectively; indifference (FICs, &gt;1.0 to \u22642.0) was observed for 26, 20, and 14% of the isolates in studies of the FLC-AmB, ITC-AmB, and SCH-AmB interactions, respectively. Antagonism (FIC &gt;2.0) was not observed. When synergy was not achieved, there was still a decrease, although not as dramatic, in the MIC of one or both drugs when they were used in combination. To investigate the effects of FLC-AmB combination therapy in vivo, we established an experimental model of systemic cryptococcosis in BALB\/c mice by intravenous injection of cells of\n            <jats:italic>C. neoformans<\/jats:italic>\n            2337, a clinical isolate belonging to serotype D against which the combination of FLC and AmB yielded an additive interaction in vitro. Both survival and tissue burden studies showed that combination therapy was more effective than FLC alone and that combination therapy was at least as effective as AmB given as a single drug. On the other hand, when cells of\n            <jats:italic>C. neoformans<\/jats:italic>\n            2337 were grown in FLC-containing medium, a pronounced increase in resistance to subsequent exposures to AmB was observed. In particular, killing experiments conducted with nonreplicating cells showed that preexposure to FLC abolished the fungicidal activity of the polyene. However, this apparent antagonism was not observed in vivo. Rather, when the two drugs were used sequentially for the treatment of systemic murine cryptococcosis, a reciprocal potentiation was often observed. Our study shows that (i) the combination of triazoles and AmB is significantly more active than either drug alone against\n            <jats:italic>C. neoformans<\/jats:italic>\n            in vitro and (ii) the concomitant or sequential use of FLC and AmB for the treatment of systemic murine cryptococcosis results in a positive interaction.\n          <\/jats:p>","DOI":"10.1128\/aac.44.9.2435-2441.2000","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T10:06:42Z","timestamp":1027764402000},"page":"2435-2441","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":66,"title":["Interactions between Triazoles and Amphotericin B against\n            <i>Cryptococcus neoformans<\/i>"],"prefix":"10.1128","volume":"44","author":[{"given":"Francesco","family":"Barchiesi","sequence":"first","affiliation":[{"name":"<!--label omitted: 1-->Istituto di Malattie Infettive e Medicina Pubblica1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M.","family":"Schimizzi","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Istituto di Malattie Infettive e Medicina Pubblica1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Caselli","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Istituto di Malattie Infettive e Medicina Pubblica1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Novelli","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->Dipartimento di Farmacologia Preclinica e Clinica, Universita\u0300 degli Studi di Firenze, Florence,2 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Fallani","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->Dipartimento di Farmacologia Preclinica e Clinica, Universita\u0300 degli Studi di Firenze, Florence,2 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Giannini","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Istituto di Malattie Infettive e Medicina Pubblica1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Arzeni","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Istituto di Malattie Infettive e Medicina Pubblica1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Di Cesare","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Istituto di Malattie Infettive e Medicina Pubblica1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi Falconi","family":"Di Francesco","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Istituto di Malattie Infettive e Medicina Pubblica1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moira","family":"Fortuna","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Istituto di Malattie Infettive e Medicina Pubblica1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Giacometti","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Istituto di Malattie Infettive e Medicina Pubblica1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Carle","sequence":"additional","affiliation":[{"name":"<!--label omitted: 3-->Centro Interdipartimentale di Epidemiologia, Biostatistica e Informatica Medica,3 Universita\u0300 degli Studi di Ancona, Ancona, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresita","family":"Mazzei","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->Dipartimento di Farmacologia Preclinica e Clinica, Universita\u0300 degli Studi di Firenze, Florence,2 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Scalise","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Istituto di Malattie Infettive e Medicina Pubblica1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.35.9.1721"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.1.226-229.2000"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/44.1.65"},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1056\/NEJM197907193010303","article-title":"A comparison of amphotericin B alone and combined with flucytosine in the treatment of criptococcal meningitis.","volume":"301","author":"Bennet J. E.","year":"1979","unstructured":"Bennet J. E. Dismukes W. E. Duma R. J. Medoff G. Sande M. A. Gallis H. A comparison of amphotericin B alone and combined with flucytosine in the treatment of criptococcal meningitis. N. Engl. J. Med. 301 1979 126 131","journal-title":"N. Engl. J. Med."},{"key":"e_1_3_2_6_2","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1056\/NEJM199401273300407","article-title":"Oral azole drugs as systemic antifungal therapy.","volume":"330","author":"Como J. A.","year":"1994","unstructured":"Como J. A. Dismukes W. E. Oral azole drugs as systemic antifungal therapy. N. Engl. J. Med. 330 1994 263 272","journal-title":"N. Engl. J. Med."},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.9.1934"},{"key":"e_1_3_2_8_2","unstructured":"Eliopoulos\n              G. M.\n              Moellering\n              R. C.\n          Antimicrobial combinations\n          Antibiotics in laboratory medicine\n          3rd ed.\n              Lorian\n              V.\n          1991\n          432\n          492\n          The Williams & Wilkins Co.\n          Baltimore Md"},{"key":"e_1_3_2_9_2","first-page":"2467","article-title":"In vitro studies of activities of the antifungal triazole SCH 56592 and itraconazole against Candida albicans,Cryptococcus neoformans, and other pathogenic yeasts.","volume":"42","author":"Galgiani J. N.","year":"1997","unstructured":"Galgiani J. N. Lewis M. L. In vitro studies of activities of the antifungal triazole SCH 56592 and itraconazole against Candida albicans,Cryptococcus neoformans, and other pathogenic yeasts. Antimicrob. Agents Chemother. 42 1997 2467 2473","journal-title":"Antimicrob. Agents Chemother."},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/168.3.692"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.38.9.2029"},{"key":"e_1_3_2_12_2","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1128\/AAC.39.7.1526","article-title":"Cross-resistance to polyene and azole drugs in Cryptococcus neoformans.","volume":"39","author":"Horne T. J.","year":"1995","unstructured":"Horne T. J. Hollomon D. Loeffler R. S. T. Kelly S. L. Cross-resistance to polyene and azole drugs in Cryptococcus neoformans. Antimicrob. Agents Chemother. 39 1995 1526 1529","journal-title":"Antimicrob. Agents Chemother."},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.8.4.515"},{"key":"e_1_3_2_14_2","unstructured":"National Clinical Committee for Clinical Laboratory Standards\n          Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard M27-A.\n          1997\n          National Committee for Clinical Laboratory Standards\n          Wayne Pa"},{"key":"e_1_3_2_15_2","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1093\/jac\/37.3.465","article-title":"Rapid high performance liquid chromatographic assay for antifungal agents in human sera.","volume":"37","author":"Ng T. K.","year":"1996","unstructured":"Ng T. K. Chan R. C. Adeyemy-Doro F. A. Cheung S. W. Cheng A. F. Rapid high performance liquid chromatographic assay for antifungal agents in human sera. J. Antimicrob. Chemother. 37 (Suppl. 3) 1996 465 472","journal-title":"J. Antimicrob. Chemother."},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.5.1120"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/146.3.429"},{"key":"e_1_3_2_18_2","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1159\/000238524","article-title":"Combination therapy of experimental candidiasis, cryptococcosis, aspergillosis and wangiellosis in mice.","volume":"33","author":"Polak A.","year":"1987","unstructured":"Polak A. Combination therapy of experimental candidiasis, cryptococcosis, aspergillosis and wangiellosis in mice. Chemotherapy (Basel) 33 1987 381 395","journal-title":"Chemotherapy (Basel)"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01568983"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.6.1345"},{"key":"e_1_3_2_21_2","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1093\/infdis\/151.5.902","article-title":"The effect of ketoconazole on amphotericin B in a model of disseminated aspergillosis.","volume":"151","author":"Schaffner A.","year":"1985","unstructured":"Schaffner A. Frick P. G. The effect of ketoconazole on amphotericin B in a model of disseminated aspergillosis. J. Infect. Dis. 151 1985 902 909","journal-title":"J. Infect. Dis."},{"key":"e_1_3_2_22_2","first-page":"371","article-title":"Antagonistic interactions between azoles and amphotericin B with yeasts depend on azole lipophilia for special test conditions in vitro.","volume":"38","author":"Scheven M.","year":"1995","unstructured":"Scheven M. Schwegler F. Antagonistic interactions between azoles and amphotericin B with yeasts depend on azole lipophilia for special test conditions in vitro. Antimicrob. Agents Chemother. 38 1995 371 373","journal-title":"Antimicrob. Agents Chemother."},{"key":"e_1_3_2_23_2","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1086\/516362","article-title":"Combination immunotherapy and antifungal chemotherapy.","volume":"26","author":"Stevens D. A.","year":"1998","unstructured":"Stevens D. A. Combination immunotherapy and antifungal chemotherapy. Clin. Infect. Dis. 26 1998 1266 1269","journal-title":"Clin. Infect. Dis."},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.35.8.1669"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.9.1907"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.3.598"},{"key":"e_1_3_2_27_2","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1086\/515319","article-title":"Interactions of itraconazole with amphotericin B in the treatment of murine invasive candidiasis.","volume":"177","author":"Sugar A. M.","year":"1998","unstructured":"Sugar A. M. Liu X. P. Interactions of itraconazole with amphotericin B in the treatment of murine invasive candidiasis. J. Infect. Dis. 177 1998 1660 1663","journal-title":"J. Infect. Dis."},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.40.11.2511"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.36.9.2690-2695.1998"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.36.3.603"},{"key":"e_1_3_2_31_2","doi-asserted-by":"crossref","first-page":"234","DOI":"10.7326\/0003-4819-104-2-234","article-title":"Cryptococcal disease in patients with the acquired immunodeficiency syndrome: diagnostic features and outcome of treatment.","volume":"104","author":"Zuger A.","year":"1986","unstructured":"Zuger A. Louie E. Holzman R. S. Simberkoff M. S. Rahal J. J. Cryptococcal disease in patients with the acquired immunodeficiency syndrome: diagnostic features and outcome of treatment. Ann. Intern. Med. 104 1986 234 240","journal-title":"Ann. Intern. Med."}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.44.9.2435-2441.2000","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.44.9.2435-2441.2000","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T16:46:59Z","timestamp":1645462019000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.44.9.2435-2441.2000"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,9]]},"references-count":30,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2000,9]]}},"alternative-id":["10.1128\/AAC.44.9.2435-2441.2000"],"URL":"https:\/\/doi.org\/10.1128\/aac.44.9.2435-2441.2000","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,9]]},"assertion":[{"value":"2000-02-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2000-06-06","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2000-09-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}