Safety and Effectiveness of Isavuconazole Treatment for Fungal Infections in Solid Organ Transplant Recipients (ISASOT Study)

We describe 53 solid organ transplant recipients treated with isavuconazole for fungal infections. Because its use in clinical practice, there is scarce data of its use in solid organ transplant recipients, where interactions with calcineurin inhibitors and mTOR and adverse drug events have limited the use of other triazoles. ABSTRACT Isavuconazole (ISA) is an alternative treatment for Aspergillus spp. and other fungal infections, but evidence regarding its use in solid organ transplant recipients (SOTR) is scarce. All SOTR who received ISA for treatment of a fungal infection (FI) at our center from December 2017 to January 2021 were included. The duration of the treatment depended on the type of infection. All patients were followed up to 3 months after treatment. Fifty-three SOTR were included, and the majority (44, 83%) were lung transplant recipients. The most frequently treated FI was tracheobronchitis (25, 46.3%). Aspergillus spp. (43, 81.1%); specially A. flavus (16, 37.2%) and A. fumigatus (12, 27.9%), was the most frequent etiology. Other filamentous fungi including one mucormycosis, and four yeast infections were treated. The median duration of treatment was 81 days (IQR 15-197). Mild gamma-glutamyltransferase elevation was the most frequent adverse event (34%). ISA was prematurely discontinued in six patients (11.3%) due to mild hepatotoxicity (2), fatigue (2), gastrointestinal intolerance (1) and myopathy (1). The mean tacrolimus dose decrease was 30% after starting ISA. Seven patients received ISA with mTOR inhibitors with good tolerability. Two patients developed breakthrough FI (3.8%). Among patients who completed the treatment, 27 (50.9%) showed clinical cure and 15 (34.1%) presented fungal persistence. Three patients (6%) died while on ISA due to FI. ISA was well tolerated and appeared to be an effective treatment for FI in SOTR. IMPORTANCE We describe 53 solid organ transplant recipients treated with isavuconazole for fungal infections. Because its use in clinical practice, there is scarce data of its use in solid organ transplant recipients, where interactions with calcineurin inhibitors and mTOR and adverse drug events have limited the use of other triazoles. To the best of our knowledge, this is the first article describing the safety regarding adverse events and drug interactions of isavuconazole for the treatment of fungal infections in a cohort of solid organ transplant recipients. Also, although this is a noncomparative study, we report some real world effectivity data of these patients, including treatment of non-Aspergillus fungal infections.

[1]  J. Vehreschild,et al.  Invasive aspergillosis in solid organ transplant patients: diagnosis, prophylaxis, treatment, and assessment of response , 2021, BMC Infectious Diseases.

[2]  G. Eschenauer,et al.  Review of Pharmacologic Considerations in the Use of Azole Antifungals in Lung Transplant Recipients , 2021, Journal of fungi.

[3]  J. Guarro,et al.  A new pleosporalean fungus isolated from superficial to deep human clinical specimens. , 2020, Medical mycology.

[4]  R. Rivosecchi,et al.  Isavuconazole is as effective as and better tolerated than voriconazole for antifungal prophylaxis in lung transplant recipients. , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[5]  Deepali Kumar,et al.  Late Onset Invasive Pulmonary Aspergillosis in Lung Transplant Recipients in the Setting of a Targeted Prophylaxis/Preemptive Antifungal Therapy Strategy , 2020, Transplantation.

[6]  J. Perfect,et al.  Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium , 2019, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[7]  D. Kontoyiannis,et al.  Lack of toxicity with long term isavuconazole use in patients with hematologic malignancy. , 2019, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[8]  D. Kontoyiannis,et al.  Therapeutic Challenges of Non-Aspergillus Invasive Mold Infections in Immunosuppressed Patients , 2019, Antimicrobial Agents and Chemotherapy.

[9]  J. Camargo,et al.  Invasive Aspergillosis in solid‐organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice , 2019, Clinical transplantation.

[10]  D. Kontoyiannis,et al.  Defining breakthrough invasive fungal infection–Position paper of the mycoses study group education and research consortium and the European Confederation of Medical Mycology , 2019, Mycoses.

[11]  G. Verleden,et al.  Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment-A consensus report from the Pulmonary Council of the ISHLT. , 2019, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[12]  R. Rivosecchi,et al.  Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients , 2018, Antimicrobial Agents and Chemotherapy.

[13]  G. Ippolito,et al.  ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid or myeloid cells surface antigens [II]: CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4). , 2018, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[14]  C. Beigelman-Aubry,et al.  Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. , 2018, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[15]  O. Manuel,et al.  Voriconazole and squamous cell carcinoma after lung transplantation: A multicenter study , 2018, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[16]  A. Groll,et al.  Drug‐drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4 , 2017, Transplant infectious disease : an official journal of the Transplantation Society.

[17]  R. Rivosecchi,et al.  Effects of Isavuconazole on the Plasma Concentrations of Tacrolimus among Solid-Organ Transplant Patients , 2017, Antimicrobial Agents and Chemotherapy.

[18]  P. Chandrasekar,et al.  Adverse effects of voriconazole: Over a decade of use , 2016, Clinical transplantation.

[19]  D. Denning,et al.  Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. , 2016, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[20]  D. Kowalski,et al.  Pharmacokinetic Assessment of Drug‐Drug Interactions of Isavuconazole With the Immunosuppressants Cyclosporine, Mycophenolic Acid, Prednisolone, Sirolimus, and Tacrolimus in Healthy Adults , 2016, Clinical pharmacology in drug development.

[21]  J. Perfect,et al.  Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. , 2016, The Lancet. Infectious diseases.

[22]  J. Baddley,et al.  Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial , 2016, The Lancet.

[23]  J. Riera,et al.  10 years of prophylaxis with nebulized liposomal amphotericin B and the changing epidemiology of Aspergillus spp. infection in lung transplantation , 2016, Transplant international : official journal of the European Society for Organ Transplantation.

[24]  P. Grossi,et al.  Invasive fungal infections in solid organ transplant recipients. , 2014, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[25]  Nina Singh,et al.  Aspergillosis in Solid Organ Transplantation , 2013, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[26]  Joseph O. Deasy,et al.  Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Based Hybrid Patient and Physician Questionnaire for Head and Neck (HN) Radiotherapy Symptom Reporting , 2011 .

[27]  M. Hannan,et al.  A 2010 working formulation for the standardization of definitions of infections in cardiothoracic transplant recipients , 2011, The Journal of Heart and Lung Transplantation.

[28]  E. Anaissie,et al.  Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.