Changes in In Vitro Susceptibility Patterns of Aspergillus to Triazoles and Correlation With Aspergillosis Outcome in a Tertiary Care Cancer Center, 1999–2015

Heo, Sang Taek; Tatara, Alexander M.; Jiménez‐Ortigosa, Cristina; Jiang, Ying; Lewis, Russell E.; Tarrand, Jeffrey; Tverdek, Frank P.; Albert, Nathaniel D.; Verweij, Paul E.; Meis, Jacques F.; Mikos, Antonios G.; Perlin, David S.; Kontoyiannis, Dimitrios P.

doi:10.1093/cid/cix297

Cited by 55 publications

(46 citation statements)

References 26 publications

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“…We also identified 4 isolates harboring mutations F46Y‐M172V‐N248T‐D255E‐E427K in different combinations, giving slightly increased POS and ISA MICs. Similar combinations, mainly associated with azole sensitivity, have been previously described in Europe, but isolates with increased azole MICs have also been reported in Europe and in the USA . Interestingly, a new mutation H285Y was also identified in one environmental isolate and was associated with pan‐azole resistance, ISA MIC being correlated with VOR MIC, as previously described for ARAF isolates with other CYP51A mutations .…”

Section: Discussionsupporting

confidence: 79%

“…Similar combinations, mainly associated with azole sensitivity, have been previously described in Europe, 32,44 but isolates with increased azole MICs have also been reported in Europe 6 and in the USA. 45 Interestingly, a new mutation H285Y was also identified in one environmental isolate and was associated with pan-azole resistance, ISA MIC being correlated with VOR MIC, as previously described for ARAF isolates with other CYP51A mutations. 46 Modeling the CYP51A indicated that the buried residue in position 285 was situated at the entrance of the ligand access channel 1.…”

Section: Discussionsupporting

confidence: 59%

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Emergence ofAspergillus fumigatusazole resistance in azole-naïve patients with chronic obstructive pulmonary disease and their homes

et al. 2017

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Azole-resistant Aspergillus fumigatus (ARAF) has been reported in patients with chronic obstructive pulmonary disease (COPD) but has not been specifically assessed so far. Here, we evaluated ARAF prevalence in azole-naïve COPD patients and their homes, and assessed whether CYP51A mutations were similar in clinical and environmental reservoirs. Sixty respiratory samples from 41 COPD patients with acute exacerbation and environmental samples from 36 of these patient's homes were prospectively collected. A. fumigatus was detected in respiratory samples from 11 of 41 patients (27%) and in 15 of 36 domiciles (42%). Cyp51A sequencing and selection on itraconazole medium of clinical (n = 68) and environmental (n = 48) isolates yielded ARAF detection in 1 of 11 A. fumigatus colonized patients with COPD (9%) and 2 of 15 A. fumigatus-positive patient's homes (13%). The clinical isolate had no CYP51A mutation. Two environmental isolates from two patients harbored TR /L98H mutation, and one had an H285Y mutation. Coexistence of different cyp51A genotypes and/or azole resistance profiles was detected in 3 of 8 respiratory and 2 of 10 environmental samples with more than one isolate, confirming the need for a systematic screening of all clinically relevant isolates. The high prevalence of ARAF in patients with COPD and their homes supports the need for further studies to assess the prevalence of azole resistance in patients with Aspergillus diseases in Northern France.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 59%

Emergence ofAspergillus fumigatusazole resistance in azole-naïve patients with chronic obstructive pulmonary disease and their homes

et al. 2017

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“…The fact that NAIMIs are uncommon diseases and that the outcome depends on multiple factors (Table 1) with a key role of nonpharmacologic parameters (e.g., stage of the fungal infection at time of diagnosis, activity of underlying disease, comorbidities, and recovery of immunosuppression) renders this assessment particularly difficult. Indeed, studies attempting to correlate MICs and outcome in opportunistic mold infections, including NAIMIs, in high-risk hematology patients are scarce (9,(12)(13)(14). Differences between in vitro artificial AST conditions and the complexity of in vivo infections are illustrated in Fig.…”

Section: In Vitro Activity Of Antifungalsmentioning

confidence: 99%

Therapeutic Challenges of Non- Aspergillus Invasive Mold Infections in Immunosuppressed Patients

Lamoth

Kontoyiannis

2019

Antimicrob Agents Chemother

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While Aspergillus spp. remain the major cause of invasive mold infections in hematologic cancer patients and transplant recipients, other opportunistic molds, such as Mucorales, Fusarium, and Scedosporium spp. are increasingly encountered in an expanding population of patients with severe and prolonged immunosuppression. High potential for tissue invasion and dissemination, resistance to multiple antifungals and high mortality rates are hallmarks of these non-Aspergillus invasive mold infections (NAIMIs). Assessment of drug efficacy is particularly difficult in the complex treatment scenarios of NAIMIs. Specifically, correlation between in vitro susceptibility and in vivo responses to antifungals is hard to assess, in view of the multiple, frequently interrelated factors influencing outcomes, such as pharmacokinetic/pharmacodynamic parameters determining drug availability at the site of infection, the net state of immune suppression, delay in diagnosis, or surgical debulking of infectious foci. Our current therapeutic approach of NAIMIs should evolve toward a better integration of the dynamic interactions between the pathogen, the drug and the host. Innovative concepts of experimental research may consist in manipulating the host immune system to induce a specific antifungal response or targeted drug delivery. In this review, we discuss the challenges in the management of NAIMIs and provide an update about the latest advances in diagnostic and therapeutic approaches.

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“…Isolates displaying resistance to clinically available antifungal agents are increasingly reported worldwide, but they are still uncommon ( 12 , 25 , 27 – 31 ). Emerging multidrug-resistant (MDR [resistant to 2 or more classes of agents]) species of Candida ( 7 , 25 , 32 , 33 ) and azole-resistant Aspergillus fumigatus ( 30 , 34 , 35 ) are now reported globally and are associated with excess health care costs in addition to considerable morbidity and mortality ( 23 , 36 , 37 ). The increase in invasive mucormycosis is especially notable as these organisms are intrinsically resistant to many antifungal agents.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Activity of Isavuconazole against Opportunistic Fungal Pathogens from Two Mycology Reference Laboratories

Pfaller

Rhomberg

Wiederhold

et al. 2018

Antimicrob Agents Chemother

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Changes in In Vitro Susceptibility Patterns of Aspergillus to Triazoles and Correlation With Aspergillosis Outcome in a Tertiary Care Cancer Center, 1999–2015

Abstract: 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.

Cited by 55 publications

References 26 publications

Emergence ofAspergillus fumigatusazole resistance in azole-naïve patients with chronic obstructive pulmonary disease and their homes

Emergence ofAspergillus fumigatusazole resistance in azole-naïve patients with chronic obstructive pulmonary disease and their homes

Therapeutic Challenges of Non- Aspergillus Invasive Mold Infections in Immunosuppressed Patients

In Vitro Activity of Isavuconazole against Opportunistic Fungal Pathogens from Two Mycology Reference Laboratories

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