{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T17:14:13Z","timestamp":1792084453494,"version":"4.4.0"},"reference-count":90,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2010,6,1]],"date-time":"2010-06-01T00:00:00Z","timestamp":1275350400000},"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":[[2010,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>To evaluate the tolerability and liver safety profiles of the systemic antifungal agents commonly used for the treatment of invasive fungal infection, we conducted a systematic review and meta-analysis of randomized controlled trials published before 31 August 2009. Two reviewers independently applied selection criteria, performed quality assessment, and extracted data. We used the beta-binomial model to account for variation across studies and the maximum likelihood method to estimate the pooled risks. We identified 39 studies with more than 8,000 enrolled patients for planned comparisons. The incidence rates of treatment discontinuation due to adverse reactions and liver injury associated with antifungal therapy ranged widely. The pooled risks of treatment discontinuation due to adverse reactions were above 10% for amphotericin B formulations and itraconazole, whereas they were 2.5% to 3.8% for fluconazole, caspofungin, and micafungin. We found that 1.5% of the patients stopped itraconazole treatment due to hepatotoxicity. Furthermore, 19.7% of voriconazole users and 17.4% of itraconazole users had elevated serum liver enzyme levels, although they did not require treatment discontinuation, whereas 2.0% or 9.3% of fluconazole and echinocandin users had elevated serum liver enzyme levels but did not require treatment discontinuation. The results were similar when we stratified the data by empirical or definitive antifungal therapy. Possible explanations for antifungal agent-related hepatotoxicity were confounded by antifungal prescription to patients with a high risk of liver injury, the increased chance of detection of hepatotoxicity due to prolonged treatment, or the pharmacological entity.<\/jats:p>","DOI":"10.1128\/aac.01657-09","type":"journal-article","created":{"date-parts":[[2010,3,23]],"date-time":"2010-03-23T01:42:20Z","timestamp":1269308540000},"page":"2409-2419","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":152,"title":["Systematic Review and Meta-Analysis of the Tolerability and Hepatotoxicity of Antifungals in Empirical and Definitive Therapy for Invasive Fungal Infection"],"prefix":"10.1128","volume":"54","author":[{"given":"Jiun-Ling","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, E-Da Hospital\/I-Shou University, Kaohsiung, Taiwan"},{"name":"Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Hsuin","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan"},{"name":"Institute of Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinong","family":"Young-Xu","sequence":"additional","affiliation":[{"name":"EpiPatterns, Haverhill, New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. Arnold","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01713042"},{"key":"e_1_3_2_3_2","first-page":"119","volume":"52","year":"1998","unstructured":"Agresti, A., and B. Coull. 1998. Approximate is better than \u2018exact\u2019 for interval estimation of binomial proportions. Am. Stat.52:119-126.","journal-title":"Am. Stat."},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/23.5.964"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/319211"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1086\/598933"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-135-6-200109180-00010"},{"key":"e_1_3_2_8_2","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1111\/j.1365-2141.2007.06906.x","volume":"140","year":"2008","unstructured":"Bow, E. J. 2008. Considerations in the approach to invasive fungal infection in patients with haematological malignancies. Br. J. Haematol.140:133-152.","journal-title":"Br. J. Haematol."},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1086\/341401"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1592\/phco.22.9.697.34072"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2007.09.016"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2007.03.021"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1177\/009286159302700242"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1086\/514341"},{"key":"e_1_3_2_15_2","unstructured":"In Biostatistics: a foundation for analysis in the health sciences 1997"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkl108"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)14472-8"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1086\/324620"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1086\/503043"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(03)00801-6"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1086\/319201"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1086\/515033"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0163-4453(95)80009-3"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(89)90441-5"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2006.09.018"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1086\/431586"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.3109\/10428190109097650"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.4065\/83.9.1011"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10096-005-0080-0"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.06.040"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1177\/1536867X0500500307"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020191"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1086\/339215"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1086\/368312"},{"key":"e_1_3_2_35_2","unstructured":"Voriconazole versus amphotericin B in cancer patients with neutropenia. 2006"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1159\/000079733"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.6.2021-2024.2004"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01728917"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)67490-9"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)60605-9"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2007.07.024"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1097\/00001432-200208000-00003"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.1998.00944.x"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkm330"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1086\/524670"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1086\/374248"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(98)00326-X"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200565140-00009"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2006.04.004"},{"key":"e_1_3_2_50_2","first-page":"1245","volume":"131","year":"1984","unstructured":"Miller, M. A. 1984. Reversible hepatotoxicity related to amphotericin B. Can. Med. Assoc. J.131:1245-1247.","journal-title":"Can. Med. Assoc. J."},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1186\/1476-0711-8-23"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(99)04149-5"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa021585"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1086\/592255"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.6.1445"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1086\/503428"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1086\/596757"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1086\/520980"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1086\/524669"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)67381-3"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1086\/497126"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1086\/343746"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.1997.2473063.x"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa066906"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199411173312001"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1086\/374850"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-7-70"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.12.3851"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.59.062906.071602"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.317.7155.379"},{"key":"e_1_3_2_71_2","first-page":"185","volume":"30","year":"2007","unstructured":"Schuler, U., S. Bammer, W. E. Aulitzky, C. Binder, A. Bohme, G. Egerer, M. Sandherr, R. Schwerdtfeger, G. Silling, H. Wandt, A. Glasmacher, and G. Ehninger. 2007. Safety and efficacy of itraconazole compared to amphotericin B as empirical antifungal therapy for neutropenic fever in patients with haematological malignancy. Onkologie30:185-191.","journal-title":"Onkologie"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200767020-00009"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1439-0507.1999.tb00023.x"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMe078078"},{"key":"e_1_3_2_75_2","first-page":"170","volume":"6","year":"2005","unstructured":"Song, J. C., and S. Deresinski. 2005. Hepatotoxicity of antifungal agents. Curr. Opin. Invest. Drugs6:170-177.","journal-title":"Curr. Opin. Invest. Drugs"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0609.2004.00239.x"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/66.3.585"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1016\/0163-4453(91)90954-Q"},{"key":"e_1_3_2_79_2","unstructured":"Reference deleted."},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01739009"},{"key":"e_1_3_2_81_2","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/0959-8049(95)00619-2","volume":"32","year":"1996","unstructured":"Viscoli, C., E. Castagnola, M. T. Van Lint, C. Moroni, A. Garaventa, M. R. Rossi, R. Fanci, F. Menichetti, D. Caselli, M. Giacchino, and M. Congiu. 1996. Fluconazole versus amphotericin B as empirical antifungal therapy of unexplained fever in granulocytopenic cancer patients: a pragmatic, multicentre, prospective and randomised clinical trial. Eur. J. Cancer32A:814-820.","journal-title":"Eur. J. Cancer"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1086\/525258"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199903113401004"},{"key":"e_1_3_2_84_2","doi-asserted-by":"publisher","DOI":"10.1086\/516353"},{"key":"e_1_3_2_85_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200201243460403"},{"key":"e_1_3_2_86_2","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1991.00400040107024"},{"key":"e_1_3_2_87_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040446"},{"key":"e_1_3_2_88_2","doi-asserted-by":"publisher","DOI":"10.1086\/514672"},{"key":"e_1_3_2_89_2","doi-asserted-by":"publisher","DOI":"10.1086\/431595"},{"key":"e_1_3_2_90_2","doi-asserted-by":"publisher","DOI":"10.1086\/317451"},{"key":"e_1_3_2_91_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(99)00457-X"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01657-09","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01657-09","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T08:04:33Z","timestamp":1711353873000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.01657-09"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,6]]},"references-count":90,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2010,6]]}},"alternative-id":["10.1128\/AAC.01657-09"],"URL":"https:\/\/doi.org\/10.1128\/aac.01657-09","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,6]]},"assertion":[{"value":"2009-11-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2010-03-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2010-06-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}