Breakthrough pulmonary Aspergillus fumigatus infection with multiple triazole resistance in a Spanish patient with chronic myeloid leukemia

Mellado, Emilia; Cámara, Rafael de la; Buendía, Buenaventura; Rodríguez-Tudela, Juan Luis; Cuenca‐Estrella, Manuel

doi:10.1016/j.riam.2012.09.002

Cited by 20 publications

(14 citation statements)

References 30 publications

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“…Isavuconazole was as effective as voriconazole and much more effective than fluconazole at reducing brain burden. All doses of isavuconazole (6,15,30,60,90, 120, or 150 mg/kg equivalent active compound) reduced brain burden (P Ͻ 0.05) in the C. krusei model and kidney burden in the C. tropicalis model (48). Another study investigated the PK/PD properties of isavuconazole in a neutropenic murine model of invasive candidiasis (IC) against clinical isolates of Candida species, including Candida albicans, Candida glabrata, and C. tropicalis, with both a 24-h and a 96-h treatment duration (48).…”

Section: Discussionmentioning

confidence: 99%

“…Voriconazole is currently recommended as a first-choice treatment for IA, and posaconazole is indicated for prophylaxis and salvage therapy (5,6). However, the management of IA has become more complicated due to the emergence of azole resistance in A. fumigatus (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Surveillance studies indicate that azole resistance is increasing in multiple European countries and in the Middle East, Asia, and Africa (17)(18)(19)(20)(21).…”

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confidence: 99%

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Pharmacodynamics of Isavuconazole in an Aspergillus fumigatus Mouse Infection Model

Seyedmousavi

Brüggemann

Meis

et al. 2015

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Pharmacodynamics of Isavuconazole in an Aspergillus fumigatus Mouse Infection Model

Seyedmousavi

Brüggemann

Meis

et al. 2015

Antimicrob Agents Chemother

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“…Similarly, the TR 34 /L98H alteration has been found in isolates from azole-naive patients in India and the TR 46 /Y121F/T289A alteration in an isolate from an azole-naive patient from Belgium (13,14). Several reports have documented in numbers the continuous spread of these "environmental" azole-resistant A. fumigatus strains in the Netherlands and in Asia (Iran, China and India) (11,(14)(15)(16)(17)(18)(19), and together they account for the vast majority of the 6.8% triazole resistance in patient samples in the Netherlands from 2009 to 2011 (20). During 2012 to 2013, the first reports documenting the presence of TR 34 /L98H in isolates from patients in Germany (21)(22)(23) and environmentally in Italy (24) have emerged.…”

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confidence: 93%

First Detection of TR ₄₆ /Y121F/T289A and TR ₃₄ /L98H Alterations in Aspergillus fumigatus Isolates from Azole-Naive Patients in Denmark despite Negative Findings in the Environment

Astvad

Jensen

Hassan

et al. 2014

Antimicrob Agents Chemother

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e Azole-resistant Aspergillus fumigatus harboring the TR 34 /L98H or TR 46 /Y121F/T289A alterations is increasingly found in Europe and Asia. Here, we present the first clinical cases of TR 46 /Y121/T289A and three cases of TR 34 /L98H outside the cystic fibrosis (CF) population in Denmark and the results of environmental surveys. Four patients (2012 to 2014) with 11 A. fumigatus and 4 Rhizomucor pusillus isolates and 239 soil samples (spring 2010 and autumn 2013, respectively) with a total of 113 A. fumigatus isolates were examined. Aspergillus isolates were screened for azole resistance using azole-containing agar. Confirmatory susceptibility testing was done using the EUCAST microbroth dilution EDEF 9.1 reference method. For relevant A. fumigatus isolates, CYP51A sequencing and microsatellite genotyping were performed. Three patients harbored TR 34 /L98H isolates. Two were azole naive at the time of acquisition and two were coinfected with wild-type A. fumigatus or R. pusillus isolates, complicating and delaying diagnosis. The TR 46 /Y121F/T289A strain was isolated in 2014 from a lung transplant patient. Genotyping indicated that susceptible and resistant Aspergillus isolates were unrelated and that no transmission between patients occurred. Azole resistance was not detected in any of the 113 soil isolates. TR 34 /L98H and TR 46 /Y121F/T289A alterations appear to be emerging in the clinical setting in Denmark and now involve azole-naive patients. Two recent soil-sampling surveys in Denmark were unable to indicate any increased prevalence of azole-resistant A. fumigatus in the environment. These findings further support the demand for real-time susceptibility testing of all clinically relevant isolates and for studies investigating the seasonal variation and ecological niches for azole-resistant environmental A. fumigatus.

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“…However, the management of IA has become more complicated due to the emergence of azole resistance in A. fumigatus (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Surveillance studies indicate that azole resistance is increasing in Europe, the Middle East, Asia, Africa, and Australia and, most recently, in North and South America as well (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30).…”

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confidence: 99%

In Vivo Efficacy of Liposomal Amphotericin B against Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates in Two Different Immunosuppression Models of Invasive Aspergillosis

Seyedmousavi

Mouton

Melchers

et al. 2017

Antimicrob Agents Chemother

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Using an immunocompetent murine model of invasive aspergillosis (IA), we previously reported that the efficacy of liposomal amphotericin B (L-AmB) (Ambisome) is not hampered by the presence of azole resistance mutations in Aspergillus fumigatus (S. Seyedmousavi, W. J. G. Melchers, J. W. Mouton, and P. E. Verweij, Antimicrob Agents Chemother 57:1866 -1871, 2013, https://doi.org/10.1128/AAC.02226 -12). We here investigated the role of immune suppression, i.e., neutropenia and steroid treatment, in L-AmB efficacy in mice infected with wild-type (WT) A. fumigatus and with azole-resistant A. fumigatus harboring a TR 34 /L98H mutation in the cyp-51A gene. Survival of treated animals at day 14 in both immunosuppressed models was significantly better than that of nontreated controls. A dose-response relationship was observed that was independent of the azole-resistant mechanism and the immunosuppression method used. In the neutropenic model, 100% survival was reached at an L-AmB dose of 16 mg/kg of body weight for the WT strain and the TR 34 /L98H isolate. In the steroid-treated group, 90.9% survival and 100% survival were achieved for the WT isolate and the TR 34 /L98H isolate with an L-AmB dose of 16 mg/kg, respectively. The 50% effective dose (ED 50 ) was 1.40 mg/kg (95% confidence interval [CI], 0.66 to 3.00 mg/kg) for the WT isolate and 1.92 mg/kg (95% CI, 0.60 to 6.17 mg/kg) for the TR 34 /L98H isolate in the neutropenic model and was 2.40 mg/kg (95% CI, 1.93 to 2.97 mg/kg) for the WT isolate and 2.56 mg/kg (95% CI, 1.43 to 4.56 mg/kg) for the TR 34 /L98H isolate in the steroid-treated group. Overall, there were no significant differences between the two different immunosuppressed conditions in the efficacy of L-AmB against the wild-type and azole-resistant isolates (P Ͼ 0.9). However, the required L-AmB exposure was significantly higher than that seen in the immunocompetent model.

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Breakthrough pulmonary Aspergillus fumigatus infection with multiple triazole resistance in a Spanish patient with chronic myeloid leukemia

Cited by 20 publications

References 30 publications

Pharmacodynamics of Isavuconazole in an Aspergillus fumigatus Mouse Infection Model

Pharmacodynamics of Isavuconazole in an Aspergillus fumigatus Mouse Infection Model

First Detection of TR ₄₆ /Y121F/T289A and TR ₃₄ /L98H Alterations in Aspergillus fumigatus Isolates from Azole-Naive Patients in Denmark despite Negative Findings in the Environment

In Vivo Efficacy of Liposomal Amphotericin B against Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates in Two Different Immunosuppression Models of Invasive Aspergillosis

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Breakthrough pulmonary Aspergillus fumigatus infection with multiple triazole resistance in a Spanish patient with chronic myeloid leukemia

Cited by 20 publications

References 30 publications

Pharmacodynamics of Isavuconazole in an Aspergillus fumigatus Mouse Infection Model

Pharmacodynamics of Isavuconazole in an Aspergillus fumigatus Mouse Infection Model

First Detection of TR 46 /Y121F/T289A and TR 34 /L98H Alterations in Aspergillus fumigatus Isolates from Azole-Naive Patients in Denmark despite Negative Findings in the Environment

In Vivo Efficacy of Liposomal Amphotericin B against Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates in Two Different Immunosuppression Models of Invasive Aspergillosis

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First Detection of TR ₄₆ /Y121F/T289A and TR ₃₄ /L98H Alterations in Aspergillus fumigatus Isolates from Azole-Naive Patients in Denmark despite Negative Findings in the Environment