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: Sang Taek Heo, Alexander M Tatara, Cristina Jiménez-Ortigosa, Ying Jiang, Russell E Lewis, Jeffrey Tarrand, Frank Tverdek, Nathaniel D Albert, Paul E Verweij, Jacques F Meis, Antonios G Mikos, David S Perlin, Dimitrios P Kontoyiannis
• Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (Clin Infect Dis) Vol. 65 Issue 2 Pg. 216-225 (Jul 15 2017) ISSN: 1537-6591 [Electronic] United States
• PMID: 28379304 (Publication Type: Journal Article)
• Copyright: © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].

Chemical References

• Antifungal Agents
• Fungal Proteins
• Triazoles
• posaconazole
• Cytochrome P-450 Enzyme System
• cytochrome P-450 CYP51A, Aspergillus
• Voriconazole
• Ergosterol

Topics

• Adult
• Antifungal Agents (pharmacology, therapeutic use)
• Aspergillosis (drug therapy, microbiology)
• Aspergillus (drug effects, genetics, isolation & purification)
• Aspergillus fumigatus (drug effects)
• Cohort Studies
• Cytochrome P-450 Enzyme System (genetics)
• Drug Resistance, Fungal (genetics)
• Ergosterol (biosynthesis)
• Female
• Fungal Proteins (genetics)
• Hematologic Neoplasms (complications, microbiology)
• Hematopoietic Stem Cell Transplantation (adverse effects)
• Humans
• Invasive Pulmonary Aspergillosis (drug therapy, microbiology, mortality)
• Male
• Microbial Sensitivity Tests
• Polymorphism, Genetic
• Prospective Studies
• Tertiary Healthcare
• Treatment Outcome
• Triazoles (pharmacology, therapeutic use)
• Voriconazole (pharmacology, therapeutic use)
• Young Adult