title: Changes in In Vitro Susceptibility Patterns of Aspergillus to Triazoles and Correlation With Aspergillosis Outcome in a Tertiary Care Cancer Center, 1999-2015.
abstract: BACKGROUND
  Azole-resistant aspergillosis in high-risk patients with hematological malignancy or hematopoietic stem cell transplantation (HSCT) is a cause of concern.
  
  
  METHODS
  We examined changes over time in triazole minimum inhibitory concentrations (MICs) of 290 sequential Aspergillus isolates recovered from respiratory sources during 1999-2002 (before introduction of the Aspergillus-potent triazoles voriconazole and posaconazole) and 2003-2015 at MD Anderson Cancer Center. We also tested for polymorphisms in ergosterol biosynthetic genes (cyp51A, erg3C, erg1) in the 37 Aspergillus fumigatus isolates isolated from both periods that had non-wild-type (WT) MICs. For the 107 patients with hematologic cancer and/or HSCT with invasive pulmonary aspergillosis, we correlated in vitro susceptibility with 42-day mortality.
  
  
  RESULTS
  Non-WT MICs were found in 37 (13%) isolates and was only low level (MIC <8 mg/L) in all isolates. Higher-triazole MICs were more frequent in the second period and were Aspergillus-species specific, and only encountered in A. fumigatus. No polymorphisms in cyp51A, erg3C, erg1 genes were identified. There was no correlation between in vitro MICs with 42-day mortality in patients with invasive pulmonary aspergillosis, irrespective of antifungal treatment. Asian race (odds ratio [OR], 20.9; 95% confidence interval [CI], 2.5-173.5; P = .005) and azole exposure in the prior 3 months (OR, 9.6; 95% CI, 1.9-48.5; P = .006) were associated with azole resistance.
  
  
  CONCLUSIONS
  Non-WT azole MICs in Aspergillus are increasing and this is associated with prior azole exposure in patients with hematologic cancer or HSCT. However, no correlation of MIC with outcome of aspergillosis was found in our patient cohort.
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston.|Department of Infectious Diseases, Jeju National University School of Medicine, Korea.
authors.forename: Sang Taek
authors.initials: ST
authors.lastname: Heo
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston.|Department of Bioengineering, Rice University, Houston, Texas.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Tatara
authors.affiliation: Public Health Research Institute-Rutgers Biomedical and Health Sciences, Newark, New Jersey.
authors.forename: Cristina
authors.initials: C
authors.lastname: Jiménez-Ortigosa
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Russell E
authors.initials: RE
authors.lastname: Lewis
authors.affiliation: Department of Microbiology.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Tarrand
authors.affiliation: Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Frank
authors.initials: F
authors.lastname: Tverdek
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Albert
authors.affiliation: Center of Expertise in Mycology, Radboudumc/Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
authors.affiliation: Center of Expertise in Mycology, Radboudumc/Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
authors.forename: Jacques F
authors.initials: JF
authors.lastname: Meis
authors.affiliation: Department of Bioengineering, Rice University, Houston, Texas.
authors.forename: Antonios G
authors.initials: AG
authors.lastname: Mikos
authors.affiliation: Public Health Research Institute-Rutgers Biomedical and Health Sciences, Newark, New Jersey.
authors.forename: David S
authors.initials: DS
authors.lastname: Perlin
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy / Q000382:microbiology; D001230:Aspergillus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D001232:Aspergillus fumigatus / Q000187:drug effects; D015331:Cohort Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D025141:Drug Resistance, Fungal / Q000235:genetics; D004875:Ergosterol / Q000096:biosynthesis; D005260:Female; D005656:Fungal Proteins / Q000235:genetics; D019337:Hematologic Neoplasms / Q000150:complications / Q000382:microbiology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy / Q000382:microbiology* / Q000401:mortality; D008297:Male; D008826:Microbial Sensitivity Tests; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D063128:Tertiary Health Care; D016896:Treatment Outcome; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D065819:Voriconazole / Q000494:pharmacology / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D014230:Triazoles; C101425:posaconazole; D003577:Cytochrome P-450 Enzyme System; C465526:cytochrome P-450 CYP51A, Aspergillus; D065819:Voriconazole; D004875:Ergosterol
keywords: aspergillosis; azole; hematology; in vitro; resistance