Breakthrough Fungal Infections in Patients With Leukemia Receiving Isavuconazole

Rausch, Caitlin R.; DiPippo, Adam J; Bose, Prithviraj; Kontoyiannis, Dimitrios P.

doi:10.1093/cid/ciy406

Cited by 75 publications

(87 citation statements)

References 14 publications

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“…In summary, these results indicate that, similar to VRC, ISAV induces a hypervirulent phenotype of Mucorales, whereas the virulence of A. fumigatus remains unaltered by ISAV. This observation, based on experiments in four Mucorales strains from three different species, may contribute to the explanation of breakthrough mucormycosis in patients receiving ISAV prophylaxis or therapy (5). Importantly, sufficient concordance of comparative virulence studies in the Drosophila model and mammalian hosts has been previously documented in experimental mucormycosis (7).…”

mentioning

confidence: 58%

Preexposure to Isavuconazole Increases the Virulence of Mucorales but Not Aspergillus fumigatus in a Drosophila melanogaster Infection Model

Wurster

Lewis

Albert

et al. 2019

Antimicrob Agents Chemother

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Breakthrough mucormycosis in patients receiving isavuconazole prophylaxis or therapy has been reported. We compared the impact of isavuconazole and voriconazole exposure on the virulence of clinical isolates of Aspergillus fumigatus and different Mucorales species in a Drosophila melanogaster infection model. In contrast to A. fumigatus, a hypervirulent phenotype was found in all tested Mucorales upon preexposure to either voriconazole or isavuconazole. These findings may contribute to the explanation of breakthrough mucormycosis in isavuconazole-treated patients.

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mentioning

confidence: 58%

Preexposure to Isavuconazole Increases the Virulence of Mucorales but Not Aspergillus fumigatus in a Drosophila melanogaster Infection Model

Wurster

Lewis

Albert

et al. 2019

Antimicrob Agents Chemother

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“…Recently, isavuconazole has been approved as first-line treatment for mucormycosis on the basis of a single-arm open-label trial showing a 67% rate of survival at day 42, which was similar to that of matched controls treated by amphotericin B formulations from an international registry (55). Experience with isavuconazole for antifungal prophylaxis is limited, but breakthrough mucormycoses have been reported, especially in the setting of refractory leukemia with persistent neutropenia (56). Correlation between in vitro MICs and clinical efficacy remains an open question regarding the Mucorales-active triazoles.…”

Section: Efficacy Of Antifungals In Vivomentioning

confidence: 86%

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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“…However, in a retro-spective study of 100 patients with leukemia receiving ISAV as a single agent for prophylaxis, breakthrough fungemia infection (BFI) developed in 13 patients (including 4 cases of mucormycosis); all BFI had prolonged neutropenia and relapse of leukemia. 254 Therapeutic drug monitoring of triazoles such as VORI and POSA has been recommended to guide therapy for IMIs, 255 but it is unclear if routine monitoring of ISAV levels is warranted given its excellent bioavailability. 256 It has been noted in a small study that levels of 2.86 mg/L after 14 days of therapy and 4.4 mg/L after 42 days of therapy were observed in seven cancer patients successfully treated for proven/probable aspergillosis or mucormycosis and that ISAV trough levels increased over time, with higher levels being associated with adverse effects.…”

Section: Prognosis Of Mucormycosismentioning

confidence: 99%

Mucormycosis

Reid

Lynch

Fishbein

et al. 2020

Semin Respir Crit Care Med

158

108

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Mucormycosis is an infection caused by a group of filamentous molds within the order Mucorales. Infections may result from ingestion of contaminated food, inhalation of spores into the nares or lungs, or inoculation into disrupted skin or wounds. In developed countries, mucormycosis occurs primarily in severely immunocompromised hosts (e.g., those with hematological malignancies, organ transplantation, neutropenia, autoimmune disorders, or other impairments in immunity). Only 6 to 10% of cases occur in subjects with no underlying disease. In contrast, in developing countries, most cases of mucormycosis occur in persons with poorly controlled diabetes mellitus or in immunocompetent subjects following trauma. Mucormycosis exhibits a marked propensity to invade blood vessels, leading to thrombosis, necrosis, and infarction of tissue. Mortality associated with invasive mucormycosis is high (> 30–50%), with 90% mortality associated with disseminated disease. Mortality rates are much lower, though still significant (10–30%), among patients with localized cutaneous disease.The diagnosis of mucormycosis relies upon histopathology and culture. Blood tests are of limited diagnostic value. Even with disseminated disease, blood cultures are usually negative. Mucorales have a distinct histological appearance, with irregular, nonseptate hyphae that branch at right angles. Cultures and/or polymerase chain reaction (PCR) are important to identify the genera.Based on anatomic localization, mucormycosis can be classified as one of six forms: (1) rhino-orbital-cerebral mucormycosis (ROCM), (2) pulmonary, (3) cutaneous, (4) gastrointestinal (GI), (5) disseminated, and (6) mucormycosis of uncommon sites. Among diabetics, ROCM is the most common clinical presentation, whereas lung involvement is uncommon. In contrast, among organ transplant recipients or patients with hematological malignancies (HemeM), pulmonary and disseminated diseases are most common. Mucormycosis can progress rapidly, and delay in initiation of treatment by even a few days markedly worsens outcomes.Due to the rarity of mucormycosis, randomized controlled therapeutic trials have not been performed. Lipid formulations of amphotericin B (LFAB) are the mainstay of therapy, but the newer triazoles, posaconazole (POSA) and isavuconazole (ISAV) (the active component of the prodrug isavuconazonium sulfate), may be effective in patients refractory to or intolerant of LFAB. Early surgical debridement or excision plays an important adjunctive role. Additional studies are required to assess the optimal duration of therapy as well as the specific roles of LFAB and the triazoles in the treatment of mucormycosis.

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Breakthrough Fungal Infections in Patients With Leukemia Receiving Isavuconazole

Cited by 75 publications

References 14 publications

Preexposure to Isavuconazole Increases the Virulence of Mucorales but Not Aspergillus fumigatus in a Drosophila melanogaster Infection Model

Preexposure to Isavuconazole Increases the Virulence of Mucorales but Not Aspergillus fumigatus in a Drosophila melanogaster Infection Model

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

Mucormycosis

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