Progressive Dispersion of Azole Resistance in Aspergillus fumigatus: Fatal Invasive Aspergillosis in a Patient with Acute Myeloid Leukemia Infected with an A. fumigatus Strain with a cyp51A TR ₄₆ Y121F M172I T289A Allele

Abstract

This Journal section presents a real, challenging case involving a multidrugresistant organism. The case authors present the rationale for their therapeutic strategy and discuss the impact of mechanisms of resistance on clinical outcome. An expert clinician then provides a commentary on the case.ABSTRACT Patients with hematologic malignancies as well as allogeneic hematopoietic stem cell transplantation (HSCT) patients are at high risk for invasive aspergillosis. Here, we report a culture-and autopsy-proven fatal invasive aspergillosis in an allogeneic HSTC patient which he developed despite posaconazole prophylaxis. The agent was determined to be an azole-resistant Aspergillus fumigatus strain bearing the cyp51A mutation combination TR 46 Y121F M172I T289A. At increasing frequency, the azole resistance of A. fumigatus is being reported globally, limiting treatment options and complicating regimens.

First azole‐resistant Aspergillus fumigatus isolates with the environmental TR46/Y121F/T289A mutation in Iran

“…We report the presence of TR 46 /Y121F/T289A now also from Iran, where until now only TR 34 /L98H had been isolated . This mutation, conferring voriconazole resistance, has been reported from both environmental (China, Taiwan, United Kingdom, Colombia, France, Germany, India, the Netherlands and Tanzania) and clinical sources (Spain, United Kingdom, France, Portugal, Argentina, Taiwan, Germany, China, Japan, United States, Denmark, Belgium and the Netherlands) (Table 1). All previous studies conducted in Iran for monitoring the mechanism of resistance among azole‐resistant A fumigatus in both clinical and environmental samples showed that the TR 34 /L98H mutation was reported with increasing frequency from 3.3% in 2013 to 6.6% in 2016 .…”

Comparison of Two Molecular Assays for Detection and Characterization of Aspergillus fumigatus Triazole Resistance and Cyp51A Mutations in Clinical Isolates and Primary Clinical Samples of Immunocompromised Patients

“…The difference in sensitivity from biopsies was also not significant ( p = 0.081). The TR46/Y121F/T289A mutation combination was found in a lung biopsy sample of a patient suffering from AML and described in Rössler et al ( 2017 ). Furthermore, we detected three L98H mutations and one TR34 alteration using our in-house ARAf PCRs with subsequent DNA sequencing.…”

“…The isolate showed the following MIC (minimum inhibitory concentration) values obtained by EUCAST reference microdilution method: voriconazole 2.0 mg/L, itraconazole >16.0 mg/L, posaconazole 0.5 mg/L (Hamprecht et al, 2012 ). The second triazole resistant TR46/Y121F/M172I/T289A positive A. fumigatus strain was from the Institute for Medical Microbiology, University Medical Center Göttingen, Göttingen, Germany (originated from the Institute of Medical Microbiology and Hygiene, Technische Universität Dresden, Dresden, Germany) and showed the following EUCAST MIC values: voriconazole >32 mg/L, itraconazole 1 mg/L, posaconazole 0.5 mg/L (Rössler et al, 2017 ). Characterization of the third multi-azole resistant TR46/Y121F/T289A positive clinical isolate (IMMi2107) from the Institute of Medical Microbiology, University Hospital Essen, Essen, Germany revealed the following EUCAST MIC values: itraconazole >16.0 mg/L, voriconazole 2 mg/L, posaconazole 0.5 mg/L (Steinmann et al, 2015 ).…”

“…In addition, we recently developed two PCR assays for the detection of the Y121F and the T289A mutations from clinical samples that are associated with the TR46 tandem repeat. Blood, BAL, biopsy, and cerebrospinal fluid (CSF) samples were previously investigated and there four TR34/L98H and one TR46/Y121F/T289A Cyp51A mutations were successfully identified in five BAL and biopsy samples (Hamprecht et al, 2012 ; Rath et al, 2012 ; Spiess et al, 2012 , 2014 ; Rössler et al, 2017 ).…”

<p>An Overview of the Management of the Most Important Invasive Fungal Infections in Patients with Blood Malignancies</p>

“… 126 Rößler (2017) Aspergillus fumigatus Invasive pulmonary aspergillosis with multiple fungal abscesses A patient in his early 70s with progressive AML AMB and voriconazole No CT scan and BAL fluid culture Died Azole resistance in A. fumigatus is an increasingly important phenomenon, leading to breakthrough infections despite prophylaxis. 127 Antonogiannaki (2019) Aspergillus species Invasive Aspergillus tracheobronchitis A 50-year-old with hairy cell leukemia and previous Plasmodium falciparum infection AMB No High resolution CT, BAL examination and direct smear Died Previous P. falciparum infection was an additional predisposing factor for the manifestation of Aspergillus infection. 128 Turki (2017) Aspergillus spp.…”