{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T15:24:47Z","timestamp":1790954687014,"version":"4.1.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T00:00:00Z","timestamp":1616371200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["71904155"],"award-info":[{"award-number":["71904155"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> The relationship between antibiotic use and the incidence of triazole-resistant phenotypes of invasive candidiasis (IC) in critically ill patients is unclear. Different methodologies on determining this relationship may yield different results.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> A retrospective multicenter observational analysis was conducted to investigate exposure to antibiotics and the incidence of non-duplicate clinical isolates of <jats:italic>Candida<\/jats:italic> spp. resistant to fluconazole, voriconazole, or both during November 2013 to April 2018, using two different methodologies: group-level (time-series analysis) and individual-patient-level (regression analysis and propensity-score adjusting).<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Of 393 identified <jats:italic>Candida<\/jats:italic> spp. from 388 critically ill patients, there were three phenotypes of IC identified: fluconazole-resistance (FR, 63, 16.0%); voriconazole-resistance (VR, 46, 11.7%); and cross-resistance between fluconazole and voriconazole (CR, 32, 8.1%). Exposure to several antibacterial agents with activity against the anaerobic gastrointestinal flora, especially third-generation cefalosporins (mainly cefoperazone\/sulbactam and ceftriaxone), but not triazoles, have an immediate effect (time lag = 0) on subsequent ICU-acquired triazole-resistant IC in the group-level (<jats:italic>p<\/jats:italic> &amp;lt; 0.05). When the same patient database was analyzed at the individual-patient-level, we found that exposure to many antifungal agents was significantly associated with triazole-resistance (fluconazole [adjusted odds ratio (aOR) = 2.73] or caspofungin [aOR = 11.32] on FR, voriconazole [aOR = 2.87] on CR). Compared to the mono-triazole-resistant phenotype, CR IC has worse clinical outcomes (14-days mortality) and a higher level of resistance.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Group-level and individual-patient-level analyses of antibiotic-use-versus-resistance relations yielded distinct but valuable results. Antibacterials with antianaerobic activity and antifungals might have \u201cindirect\u201d and \u201cdirect\u201d effect on triazole-resistant IC, respectively.<\/jats:p>","DOI":"10.3389\/fphar.2021.586893","type":"journal-article","created":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T06:54:56Z","timestamp":1616396096000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["ICU Patients\u2019 Antibiotic Exposure and Triazole-Resistance in Invasive Candidiasis: Parallel Analysis of Aggregated and Individual Data"],"prefix":"10.3389","volume":"12","author":[{"given":"Yan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Treasure M.","family":"McGuire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha A.","family":"Hollingworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mieke L.","family":"Van Driel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalin","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.jinf.2015.09.041","article-title":"Impact of antifungal prescription on relative distribution and susceptibility of candida spp.\u2014trends over 10 years","volume":"72","author":"Bailly","year":"2016","journal-title":"J. Infect."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2518","DOI":"10.1128\/AAC.05947-11","article-title":"Antibiotic exposure as a risk factor for fluconazole-resistant candida bloodstream infection","volume":"56","author":"Ben-Ami","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"B3","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1001\/jama.2009.153","article-title":"Methicillin-resistant staphylococcus aureus central line-associated bloodstream infections in us intensive care units, 1997-2007","volume":"301","author":"Burton","year":"2009","journal-title":"JAMA"},{"key":"B4","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1186\/s13054-016-1313-6","article-title":"Diagnosis and management of invasive candidiasis in the icu: an updated approach to an old enemy","volume":"20","author":"Calandra","year":"2016","journal-title":"Crit. Care"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1046\/j.1365-2958.2002.02814.x","article-title":"A common drug-responsive element mediates the upregulation of the candida albicans abc transporters cdr1 and cdr2, two genes involved in antifungal drug resistance","volume":"43","author":"de Micheli","year":"2002","journal-title":"Mol. Microbiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"4554","DOI":"10.1073\/pnas.1000087107","article-title":"Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation","volume":"108","author":"Dethlefsen","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1925","DOI":"10.1056\/NEJM200012283432604","article-title":"Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients","volume":"343","author":"Donskey","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.3201\/eid2011.140685","article-title":"Drug-resistant candida glabrata infection in cancer patients","volume":"20","author":"Farmakiotis","year":"2014","journal-title":"Emerging Infect. Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1097\/CCM.0000000000002867","article-title":"Initial antifungal strategy reduces mortality in critically ill patients with candidemia: a propensity score-adjusted analysis of a multicenter study","volume":"46","author":"Garnacho-Montero","year":"2018","journal-title":"Crit. Care Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1660","DOI":"10.1093\/jac\/dkt083","article-title":"Invasive candidiasis in intensive care units in China: a multicentre prospective observational study","volume":"68","author":"Guo","year":"2013","journal-title":"J. Antimicrob. Chemother."},{"key":"B11","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.jhin.2013.06.002","article-title":"Possible transmission of candida albicans on an intensive care unit: genotype and temporal cluster analyses","volume":"85","author":"Hammarskj\u00f6ld","year":"2013","journal-title":"J. Hosp. Infect."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.1086\/322677","article-title":"Parallel analysis of individual and aggregated data on antibiotic exposure and resistance in gram-negative bacilli","volume":"33","author":"Harbarth","year":"2001","journal-title":"Clin. Infect. Dis."},{"key":"B13","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1177\/096228029600500102","article-title":"Box-jenkins modelling in medical research","volume":"5","author":"Helfenstein","year":"1996","journal-title":"Stat. Methods Med. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1097\/CCM.0000000000000746","article-title":"Invasive candida infections and the harm from antibacterial drugs in critically ill patients: data from a randomized, controlled trial to determine the role of ciprofloxacin, piperacillin-tazobactam, meropenem, and cefuroxime","volume":"43","author":"Jensen","year":"2015","journal-title":"Crit. Care Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"4555","DOI":"10.1128\/AAC.49.11.4555-4560.2005","article-title":"Prior antimicrobial therapy and risk for hospital-acquired candida glabrata and candida krusei fungemia: a case-case-control study","volume":"49","author":"Lin","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"B16","doi-asserted-by":"publisher","first-page":"347","DOI":"10.3201\/eid0804.010312","article-title":"Antimicrobial use and antimicrobial resistance: a population perspective","volume":"8","author":"Lipsitch","year":"2002","journal-title":"Emerging Infect. Dis."},{"key":"B17","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/s0924-8579(99)00135-1","article-title":"Modelling and forecasting antimicrobial resistance and its dynamic relationship to antimicrobial use: a time series analysis","volume":"14","author":"L\u00f3pez-Lozano","year":"2000","journal-title":"Int. J. Antimicrob. Agents"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1007\/s00134-014-3408-3","article-title":"Worrisome trends in incidence and mortality of candidemia in intensive care units (paris area, 2002-2010)","volume":"40","author":"Lortholary","year":"2014","journal-title":"Intensive Care Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1007\/s00134-019-05599-w","article-title":"Esicm\/escmid task force on practical management of invasive candidiasis in critically ill patients","volume":"45","author":"Martin-Loeches","year":"2019","journal-title":"Intensive Care Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1097\/MCC.0000000000000124","article-title":"Risks for multidrug-resistant pathogens in the icu","volume":"20","author":"Mart\u00edn-Loeches","year":"2014","journal-title":"Curr. Opin. Crit. Care"},{"key":"B21","doi-asserted-by":"publisher","first-page":"18026","DOI":"10.1038\/nrdp.2018.26","article-title":"Invasive candidiasis","volume":"4","author":"Pappas","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"B22","doi-asserted-by":"publisher","first-page":"S612","DOI":"10.1093\/cid\/civ791","article-title":"Echinocandin resistance in candida","volume":"61","author":"Perlin","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e383","DOI":"10.1016\/S1473-3099(17)30316-X","article-title":"The global problem of antifungal resistance: prevalence, mechanisms, and management","volume":"17","author":"Perlin","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"B24","doi-asserted-by":"publisher","first-page":"4690","DOI":"10.1128\/AAC.03255-14","article-title":"Role of fks mutations in candida glabrata: mic values, echinocandin resistance, and multidrug resistance","volume":"58","author":"Pham","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"B25","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1128\/AAC.49.1.438-440.2005","article-title":"Effect of parenteral antibiotic administration on establishment of intestinal colonization by candida glabrata in adult mice","volume":"49","author":"Pultz","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"B26","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1128\/CMR.00001-13","article-title":"Epidemiological interpretation of studies examining the effect of antibiotic usage on resistance","volume":"26","author":"Schechner","year":"2013","journal-title":"Clin. Microbiol. Rev."},{"key":"B27","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1177\/0272989X0102100106","article-title":"Prognostic modeling with logistic regression analysis: in search of a sensible strategy in small data sets","volume":"21","author":"Steyerberg","year":"2001","journal-title":"Med. Decis. Making"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2867","DOI":"10.1093\/jac\/dky270","article-title":"Trends in antifungal use in us hospitals, 2006-12","volume":"73","author":"Vallabhaneni","year":"2018","journal-title":"J. Antimicrob. Chemother."},{"key":"B29","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1093\/jac\/dkq525","article-title":"Modelling the impact of antibiotic use on antibiotic-resistant escherichia coli using population-based data from a large hospital and its surrounding community","volume":"66","author":"Vernaz","year":"2011","journal-title":"J. Antimicrob. Chemother."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2323","DOI":"10.1001\/jama.2009.1754","article-title":"International study of the prevalence and outcomes of infection in intensive care units","volume":"302","author":"Vincent","year":"2009","journal-title":"JAMA"},{"key":"B31","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.ijid.2019.10.016","article-title":"Antifungal agents for invasive candidiasis in non-neutropenic critically ill adults: what do the guidelines recommend?","volume":"89","author":"Wang","year":"2019","journal-title":"Int. J. Infect. Dis."},{"key":"B32","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1093\/jac\/dkq046","article-title":"Polymyxin b, in combination with fluconazole, exerts a potent fungicidal effect","volume":"65","author":"Zhai","year":"2010","journal-title":"J. Antimicrob. Chemother."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.586893\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T06:54:59Z","timestamp":1616396099000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.586893\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,22]]},"references-count":32,"alternative-id":["10.3389\/fphar.2021.586893"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.586893","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,22]]},"article-number":"586893"}}