isavuconazole and Pulmonary-Aspergillosis

Severe acute respiratory syndrome coronavirus 2 causes direct damage to the airway epithelium, enabling aspergillus invasion. Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported. This article constitutes a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, prepared by experts and endorsed by medical mycology societies. COVID-19-associated pulmonary aspergillosis is proposed to be defined as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Recommended first-line therapy is either voriconazole or isavuconazole. If azole resistance is a concern, then liposomal amphotericin B is the drug of choice. Our aim is to provide definitions for clinical research and up-to-date recommendations for clinical management of the diagnosis and treatment of COVID-19-associated pulmonary aspergillosis.

Topics: Amphotericin B; Antifungal Agents; Azoles; Coinfection; COVID-19; Humans; Nitriles; Pulmonary Aspergillosis; Pyridines; SARS-CoV-2; Triazoles; Voriconazole

Chronic pulmonary aspergillosis (CPA) is a chronic lung infection caused by. We discuss the approach to diagnosis and treatment of CCPA. We have searched the PubMed and EmBase databases (from inception till 31 October 2019) to identify studies describing the use of anti-fungal agents in CCPA.. Treatment for CCPA should be initiated with oral itraconazole for at least six months. In case of poor response or intolerance to itraconazole, voriconazole should be considered. Intravenous agents, including amphotericin B and echinocandins, may be used in those with either treatment failure or those who are intolerant to oral antifungal agents. Posaconazole and isavuconazole may be used as salvage therapy due to a better pharmacokinetic/pharmacodynamic profile of the former and reduced drug-drug interactions with the latter.

Topics: Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Disease Management; Echinocandins; Humans; Itraconazole; Nitriles; Practice Guidelines as Topic; Pulmonary Aspergillosis; Pyridines; Triazoles; Voriconazole

Notable progress has been made in the past years in the classification, diagnosis and treatment of pulmonary aspergillosis. New criteria were proposed by the Working Group of the International Society for Human and Animal Mycology (ISHAM) for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA). The latest classification of chronic pulmonary aspergillosis (CPA) suggested by the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) has become widely accepted among clinicians. Subacute invasive pulmonary aspergillosis is now considered a type of CPA, yet it is still diagnosed and treated similarly to invasive pulmonary aspergillosis (IPA). Isavuconazole, an extended-spectrum triazole, has recently been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of IPA. The most recent Infectious Diseases Society of America (IDSA) guidelines strongly recommend reducing mold exposure to patients at high risk for pulmonary aspergillosis. The excessive relapse rate following discontinuation of therapy remains a common reality to all forms of this semi-continuous spectrum of diseases. This highlights the need to continuously reassess patients and individualize therapy accordingly. Thus far, the duration of therapy and the frequency of follow-up have to be well characterized.

Topics: Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Aspergillus; Environmental Exposure; Fungi; Humans; Invasive Pulmonary Aspergillosis; Nitriles; Prognosis; Pulmonary Aspergillosis; Pyridines; Recurrence; Triazoles

Triazole antifungal drugs may rarely cause serious allergic reactions including angioedema. No standardized tests are available to predict cross-reactivity within the azole class and little guiding information exists on whether to change therapy within the class or to another class after a serious allergic reaction. Herein we report the first successful use, to our knowledge, of graded isavuconazole introduction for treatment of aspergillosis in a liver transplant recipient with severe voriconazole allergy.

Topics: Amphotericin B; Angioedema; Antifungal Agents; Aspergillus; Desensitization, Immunologic; Drug Administration Schedule; Drug Hypersensitivity; Female; Humans; Liver Cirrhosis; Liver Transplantation; Lung; Middle Aged; Nitriles; Pulmonary Aspergillosis; Pyridines; Tomography, X-Ray Computed; Treatment Outcome; Triazoles; Voriconazole

Isavuconazole is a convenient triazole antifungal agent with a broad antifungal spectrum. A randomized, open-label study (ClinicalTrials.gov, NCT03471988) was conducted to evaluate the efficacy and safety of isavuconazole in Japanese patients with deep-seated mycoses.. In Cohort A, patients with aspergillosis (chronic pulmonary aspergillosis and invasive aspergillosis) were randomized in a 2:1 ratio to isavuconazole or voriconazole, and in Cohort B, patients with cryptococcosis and mucormycosis were assigned to isavuconazole for up to 84 days of treatment. The overall outcome was evaluated according to the clinical, radiological, and mycological responses at Days 42 and 84 and at the end of treatment (EOT).. A total of 103 participants were enrolled and received the study drug. The overall response rate of patients with chronic pulmonary aspergillosis in the isavuconazole (52 patients) and voriconazole (27 patients) groups was 82.7% and 77.8% at EOT, respectively. The response rate in patients with cryptococcosis (10 patients, isavuconazole group only) was 90.0%. One of three participants with invasive aspergillosis and one of three participants with mucormycosis responded in the isavuconazole group. In the safety evaluation, the incidence of adverse events in participants with chronic pulmonary aspergillosis was similar in both groups. Adverse drug reactions were reported in 32 (61.5%) patients receiving isavuconazole and 23 (85.2%) patients receiving voriconazole.. Isavuconazole showed efficacy and safety in Japanese patients with chronic pulmonary aspergillosis and cryptococcosis, for which the drug is not currently indicated.

Topics: Antifungal Agents; Aspergillosis; Cryptococcosis; Humans; Invasive Fungal Infections; Japan; Mucormycosis; Pulmonary Aspergillosis; Triazoles; Voriconazole

A 67-year-old obese man (BMI 38.0) with type 2 diabetes mellitus (DM), chronic atrial fibrillation, and chronic lymphocytic leukemia stage II, stable for 8 years after chemotherapy, and a history of smoking presented to the ED with progressive dyspnea and fever due to SARS-CoV-2 infection. He was admitted to a general ward and treated with dexamethasone (6 mg IV once daily) and oxygen. On day 3 of hospital admission, he became progressively hypoxemic and was admitted to the ICU for invasive mechanical ventilation. Dexamethasone treatment was continued, and a single dose of tocilizumab (800 mg) was administered. On day 9 of ICU admission, voriconazole treatment was initiated after tracheal white plaques at bronchoscopy, suggestive of invasive Aspergillus tracheobronchitis, were noticed. However, his medical situation dramatically deteriorated.

Topics: Acute Kidney Injury; Aged; Amphotericin B; Antibodies, Monoclonal, Humanized; Antifungal Agents; Atrial Fibrillation; Bronchoscopy; COVID-19; Dexamethasone; Diabetes Mellitus, Type 2; Fatal Outcome; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Mucormycosis; Nitriles; Obesity; Oxygen Inhalation Therapy; Pulmonary Aspergillosis; Pyridines; Respiration, Artificial; SARS-CoV-2; Smoking; Tomography, X-Ray Computed; Triazoles; Voriconazole

Patients with acute respiratory distress syndrome (ARDS) due to viral infection are at risk for secondary complications like invasive aspergillosis. Our study evaluates coronavirus disease 19 (COVID-19) associated invasive aspergillosis at a single centre in Cologne, Germany.. A retrospective chart review of all patients with COVID-19 associated ARDS admitted to the medical or surgical intensive care unit at the University Hospital of Cologne, Cologne, Germany.. COVID-19 associated invasive pulmonary aspergillosis was found in five of 19 consecutive critically ill patients with moderate to severe ARDS.. Clinicians caring for patients with ARDS due to COVID-19 should consider invasive pulmonary aspergillosis and subject respiratory samples to comprehensive analysis to detect co-infection.

Topics: Aged; Antifungal Agents; Bronchoalveolar Lavage Fluid; Coronavirus Infections; COVID-19; Female; Galactose; Germany; Hemorrhage; Hospitals, Teaching; Humans; Intensive Care Units; Lung Diseases; Male; Mannans; Metapneumovirus; Middle Aged; Nitriles; Pandemics; Paramyxoviridae Infections; Pneumonia, Viral; Pulmonary Aspergillosis; Pyridines; Respiratory Distress Syndrome; Retrospective Studies; Thorax; Tomography, X-Ray Computed; Triazoles; Voriconazole

Invasive aspergillosis in hematologic pediatric patients is an opportunistic infection that is difficult to treat, with a high mortality rate when localized in the central nervous system. We are describing a 3-year-old girl who was affected by acute lymphoblastic leukemia who developed cerebral and pulmonary aspergillosis during induction chemotherapy. The patient failed first-line voriconazole treatment because of being a CYP2C19 ultrarapid metabolizer and received effective isavuconazole therapy with no notable side effects.

Topics: Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillus; Child, Preschool; Female; Humans; Neuroaspergillosis; Nitriles; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Pulmonary Aspergillosis; Pyridines; Triazoles

We present 2 fatal cases of invasive fungal disease with isavuconazole treatment failure in immunocompromised patients: one with a TR34-L98H azole-resistant Aspergillus fumigatus isolate and the other a Rhizomucor-A. fumigatus co-infection. Such patients probably require surveillance by galactomannan antigen detection and quantitative PCRs for A. fumigatus and Mucorales fungi.

Topics: Antifungal Agents; Aspergillus fumigatus; Diagnosis, Differential; Fatal Outcome; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Male; Middle Aged; Nitriles; Pulmonary Aspergillosis; Pyridines; Treatment Failure; Triazoles

Long-term oral triazole antifungal therapy is the cornerstone of management for patients with chronic pulmonary aspergillosis (CPA). Itraconazole is the first-line choice of treatment. Voriconazole, posaconazole or isavuconazole can be used as alternative treatments in case of resistance or intolerance. All of these can cause significant adverse drug reactions.. To evaluate how CPA patients tolerate voriconazole and isavuconazole after prior triazole therapy.. We performed a retrospective observational study at the UK National Aspergillosis Centre. Medical records for all consecutive CPA patients started on isavuconazole and voriconazole during an observation period of 12 and 6 months respectively were analysed.. During this study period, 20 patients were started on isavuconazole and 21 patients on voriconazole. Adverse events were seen in 18 of 21 (86%) the patients in the voriconazole group and 12 of 20 (60%) in the isavuconazole group (P = 0.02). For those who developed adverse events to these agents, the rates of discontinuation of therapy were comparable (ie 10/18 [56%], voriconazole vs 8/12 [67%], isavuconazole; P = 0.54). Five (25%) patients in the isavuconazole group who were intolerant to other triazoles tolerated the standard dose of isavuconazole.. Compared with isavuconazole, adverse events were significantly higher in CPA patients commenced on voriconazole. Isavuconazole may be an option for those patients who are intolerant to other triazoles.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Chronic Disease; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Nitriles; Pulmonary Aspergillosis; Pyridines; Retrospective Studies; Triazoles; United Kingdom; Voriconazole