Efficacy and safety of Isavuconazole for the treatment of invasive Aspergillus infection - an update of the literature.

INTRODUCTION: Invasive aspergillosis is associated with high morbidity and mortality in immunocompromised patients. It is now increasingly reported in critically ill patients, including those with respiratory viral infections, such as influenza and COVID-19. Antifungal management is challenging due to diagnostic delay, adverse drug reactions, drug-drug interactions, narrow therapeutic window, and the emergence of resistance. Isavuconazole is the most recent FDA approved azole for the treatment of invasive aspergillosis, with data continuing to accumulate. AREAS COVERED: The authors review the safety and efficacy of isavuconazole in the management of invasive aspergillosis based on the currently available evidence. The authors also report on the structure, mechanism of action, pharmacokinetic properties, in vitro and in vivo studies as well as clinical safety and efficacy reports of isavuconazole since its FDA approval. EXPERT OPINION: Isavuconazole is non-inferior to voriconazole and is a safe, effective, and better tolerated option for the treatment of invasive aspergillosis. It offers several advantages over other antifungal agents, including having a better adverse event profile with respect to hepatotoxicity, neuro-visual toxicity, QTc prolongation, as well as a stable pharmacokinetic profile obviating the need for therapeutic drug monitoring. Further studies are needed to evaluate its performance in prophylaxis against invasive aspergillosis as well as in the treatment of aspergillosis in critically ill patients without underlying cancer or transplant.

Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib.

Ibrutinib has revolutionized the management of chronic lymphocytic leukemia and is now being increasingly used. Although considered to be less immunosuppressive than conventional immunochemotherapy, the observation of a few cases of invasive fungal infections in patients treated with ibrutinib prompted us to conduct a retrospective survey. We identified 33 cases of invasive fungal infections in patients receiving ibrutinib alone or in combination. Invasive aspergillosis (IA) was overrepresented (27/33) and was associated with cerebral localizations in 40% of the cases. Remarkably, most cases of invasive fungal infections occurred with a median of 3 months after starting ibrutinib. In 18/33 cases, other conditions that could have contributed to decreased antifungal responses, such as corticosteroids, neutropenia, or combined immunochemotherapy, were present. These observations indicate that ibrutinib may be associated with early-onset invasive fungal infections, in particular IA with frequent cerebral involvement, and that patients on ibrutinib should be closely monitored in particular when other risk factors of fungal infections are present.

Cutaneous invasive aspergillosis in a patient with glioblastoma receiving long-term temozolomide and corticosteroid therapy.

Glioblastoma is an aggressive brain tumor that requires multidisciplinary treatment including adjuvant radiotherapy, chemotherapy, and adjunct corticosteroids. Temozolomide is a commonly used chemotherapy drug and frequently causes lymphocytopenia. We describe the case of a 67-year-old woman with cutaneous invasive aspergillosis who had received long-term temozolomide and corticosteroid therapy for glioblastoma. She presented with multiple indurations, erythema, and purpura, some of which produced purulent discharge, in the anterior abdomen. Extensive intra- or inter-muscular abscesses of the right anterior abdominal wall were also observed. Her absolute lymphocyte counts were 156/µL on admission. Cultures obtained from the wound yielded Aspergillus fumigatus. She was diagnosed with secondary cutaneous invasive aspergillosis, which likely resulted from hematogenous dissemination. Although rare, this case illustrates that temozolomide-induced lymphocytopenia, especially in cases of concomitant corticosteroid use, can be associated with severe invasive aspergillosis.

Orbital Apex Syndrome Caused by Invasive Aspergillosis as an Adverse Effect of Systemic Chemotherapy for Metastatic Colorectal Cancer: a Case Report.

Continuous therapy with cytotoxic drugs suppresses humoral immune function and may result in local infection. We present a case of orbital apex syndrome caused by Aspergillus infection during chemotherapy for metastatic colorectal cancer. A 74-year-old man with colorectal liver metastases under long-term continuous systemic chemotherapy presented with painful, progressive orbital apex syndrome. Magnetic resonance imaging disclosed a small enhancing lesion around the right ethmoid sinus. We initially diagnosed colorectal cancer metastasis and he underwent biopsy via the endoscopic endonasal transethmoid approach. However, pathological examination of the cultured specimen revealed Aspergillus fumigatus. The patient was treated with voriconazole and the orbital apex syndrome resolved after 1 month. Orbital aspergillosis is a life-threatening disease and should be listed as a differential diagnosis of uncommon local infections during continuous chemotherapy.

Voriconazole Exposure and Risk of Cutaneous Squamous Cell Carcinoma, Aspergillus Colonization, Invasive Aspergillosis and Death in Lung Transplant Recipients.

Voriconazole is a triazole antifungal used to prevent and treat invasive fungal infections after lung transplantation, but it has been associated with an increased risk of developing cutaneous squamous cell carcinoma (SCC). Despite widespread use, there are no clear guidelines for optimal prophylactic regimens that balance the competing risks and benefits. We conducted a retrospective cohort study of all lung transplant recipients at the University of California, San Francisco, who were transplanted between October 1991 and December 2012 (n = 455) to investigate whether voriconazole exposure affected development of SCC, Aspergillus colonization, invasive aspergillosis and all-cause mortality. Voriconazole exposure was associated with a 73% increased risk of developing SCC (hazard ratio [HR] 1.73; 95% confidence interval [CI]: 1.04-2.88; p = 0.03), with each additional 30-day exposure at the standard dose increasing the risk by 3.0% (HR 1.03; 95% CI: 1.02-1.04; p < 0.001). Voriconazole exposure reduced risk of Aspergillus colonization by 50% (HR 0.50; 95% CI: 0.34-0.72; p < 0.001), but we were underpowered to detect risk reduction for invasive aspergillosis. Voriconazole exposure significantly reduced all-cause mortality among subjects who developed Aspergillus colonization (HR 0.34; 95% CI: 0.13-0.91; p = 0.03) but had no significant impact on those without colonization. Physicians should consider patient-specific factors that modify the potential risks and benefits of voriconazole for the care of lung transplant recipients.

Brain Abscesses Due to Aspergillus nidulans Infection During Induction Chemotherapy for Acute Lymphoblastic Leukemia.

We present the case of a 3-year-old boy who was diagnosed with cerebral abscesses due to Aspergillus nidulans infection on day 28 of induction chemotherapy for acute lymphoblastic leukemia. He responded well to treatment with voriconazole and caspofungin, making a full recovery. There are very few cases of invasive aspergillosis reported in children during induction chemotherapy for acute leukemia and A. nidulans is rare in the absence of chronic granulomatous disease.

[Invasive orbital aspergillosis: Rare but important differential diagnosis in the case of immunosuppression]. / Invasive Aspergillose der Orbita: Seltene, aber wichtige Differenzialdiagnose bei Immunsuppression.

Invasive aspergillosis originating from the paranasal sinuses is a rare disease that is associated with high mortality rates. We report on a 77-year-old patient with myelodysplastic syndrome and progressive left-sided proptosis persisting for 5 days. Antibiotic therapy and endonasal orbital decompression yielded insufficient improvement. Only upon application of complementary antifungal therapy was remission observed. Rapid diagnosis and treatment are essential in order to prevent life-threatening complications.

Primary aspergillosis of vocal cord: Long-term inhalational steroid use can be the miscreant.

Primary laryngeal aspergillosis is extremely rare, especially in an immunocompetent host. It is commonly found as a part of systemic infection in immunocompromised patients. A case of vocal cord aspergillosis with no systemic extension in an immunocompetent patient on long-term steroid metered dose inhaler (MDI) is presented here, because of its rarity. The present case is a 28-year-old asthmatic female who was on inhalational steroid for 8 years, presented with sudden onset of severe dysphonia for 5 days. Fiberoptic laryngoscopy demonstrated whitish plaque involving right vocal cord, clinically suggestive of fungal laryngitis. Microlaryngeal laser surgery was performed with stripping of the plaque. Histopathology demonstrated ulcerated hyperplastic squamous epithelium with masses of fungal hyphae, which was confirmed to be Aspergillus species on fungal culture. This rare but serious adverse effect of long-term steroid MDI use must be kept in mind while treating an asthmatic patient. We also present a brief review of literature of laryngeal aspergillosis.

Invasive fungal sinusitis in a healthy athlete due to long-term anabolic steroid use.

Invasive fungal rhinosinusitis is a potentially fatal infection that affects immunocompromised patients. Prognosis is generally poor despite aggressive medical and surgical treatments. We present the first reported case of invasive fungal sinusitis in a healthy 18-year-old male athlete who was taking anabolic androgenic steroids (AAS). The effects of excessive AAS use on the immune system are not fully understood, but there may be consequences at supraphysiological concentrations. This case demonstrates potential immunomodulatory effects of anabolic steroids and highlights a previously unknown cause of invasive fungal sinusitis.

Pharmacogenetics and beyond: variability of voriconazole plasma levels in a patient with primary immunodeficiency.

We report the case of a patient highly susceptible to invasive aspergillosis who received treatment with voriconazole (VRC). As part of therapeutic drug monitoring, VRC plasma trough concentrations were measured, showing undetectable levels (<0.16 µg/ml). Genotyping showed a heterozygous profile CYP2C19*1/*17, known to be associated with an ultrarapid-metabolism phenotype, contributing to the very low systemic exposure observed. Therefore, in this situation, the use of VRC treatment could be associated with therapeutic failure.

Emergency hemicolectomy for intestinal primary aspergillosis in acute myeloid leukemia.

Intestinal aspergillosis is an infection with a very high death rate especially in leukemic patients. Here we describe a case of a 46 years old woman with acute myeloid leukemia (LAM M5) who developed intestinal primary aspergillosis. This patient was diagnosed with LAM M5 through bone marrow aspiration and bone biopsy in March 2004. Symptoms of the disease were slight persistent fever, weight loss, asthenia, anemia, thrombocytopenia,and leukocytosis with high number of blasts in peripheral blood. After induction chemotherapy with ICE (Ifosfamide, Carboplatin, Etoposide), she developed neutropenia and high fever without apparent infective foci. She was treated with empiric antibiotic therapy, nevertheless she developed an intense diarrhea and ileo-cecal distention. Diagnostic exams didn't show signs of a focal lesion. Despite the change in antibiotic treatment and the transfusions of granulocytes and blood cells, the patient developed extremely critical conditions with persistence of neutropenia and abdominal distention. A surgical treatment was decided at the time. We treated the patient with a two steps surgical procedure. The first step was a right abdominal ileostomy followed by improvement of general conditions and then the second step a right colectomy. The histological morphology confirmed necrotizing colitis with Aspergillus ife. At that time , treatment with voriconazole was started. The general conditions of the patient improved rapidly and we were able to treat the patient with other medical anti-leukemic therapies. The patient is now cured and in healthy state. We obtained a good clinical result as only in other few cases described in literature.

Nasal eschar: a warning sign of potentially fatal invasive fungal sinusitis in immunocompromised children.

Most invasive fungal sinusitis occurs in immunocompromised adult patients. We present the case study of a 12-year-old boy diagnosed with acute myeloblastic leukemia undergoing chemotherapy. He developed a progressive darkening discoloration over the dorsum of the nose that turned into an eschar. Nasal endoscopy revealed extensive necrotic tissue in the nasal cavity mucosa, inferior and middle turbinates, and septal cartilage that extended to the eschar of the skin over the nasal dorsum. Histopathology showed aspergillus invasive fungal rhinosinusitis.

[Triple fungal infection in a patient with liver cirrhosis]. / Triple infection fongique chez un patient avec cirrhose hépatique.

The prevalence of invasive mycoses is increasing, especially among patients who are immunocompromised or hospitalized with serious underlying diseases. Such infections are associated with a high morbidity and significant mortality, requiring early diagnosis and appropriate treatment but also an optimal prophylaxis in patients with high risk factors. We report a case of triple fungal infection including an invasive pulmonary aspergillosis by Aspergillus fumigatus, a candidemia by Candida albicans and a Pneumocystis pneumonia. The overall clinical picture of this patient was liver cirrhosis with medical history of immunosuppressive treatment for Crohn disease and a non-hodgkin lymphoma. There was no antifungal prophylaxis for this patient. Under treatment, the issue was unfavourable with multivisceral failure.

Effects of Saccharomyces cerevisiae extract on haematological parameters, immune function and the antioxidant defence system in breeder hens fed aflatoxin contaminated diets.

The study was conducted to investigate the efficacy of Saccharomyces cerevisiae extract (SC) on haematological parameters, immune function, and the antioxidant defence system in breeder hens fed a diet contaminated with low level aflatoxin (AF). Forty-eight Ross 308 breeder hens were fed on diets containing AF (0 or 100 µg/kg) and SC (0 or 1 g/kg) in a 2 × 2 factorial arrangement. Red blood cell (RBC), white blood cell (WBC), and platelet counts, differential leucocyte counts, blood CD3+, CD4+, CD8+ and CD5+ T cell ratios, phagocytic activity and oxidative burst of heterophils, plasma and liver catalase activity, and malondialdehyde (MDA) and ascorbic acid concentrations were measured. 3. Plasma and liver MDA concentrations increased (P < 0·05), liver catalase activity decreased (P < 0·05) and total WBC count tended to decrease (P = 0·082) in hens fed the contaminated diet. WBC count, monocyte percentage, phagocytic activity and oxidative burst of heterophils increased (P < 0·05), and plasma MDA concentration tended to decrease (P = 0.088) in SC extract supplemented hens. There was a significant interaction between AF and SC on heterophil, lymphocyte, CD5+ cell percentages, and plasma catalase activity. Blood heterophil percentage decreased but lymphocyte percentage increased in hens fed on the AF contaminated diet without SC supplementation. SC supplementation counteracted the negative effect of AF on heterophils and lymphocytes. The CD5+ cell percentage decreased in unsupplemented hens fed the AF contaminated diet and this negative effect was minimised in SC supplemented hens. Plasma catalase activity increased in SC supplemented hens fed the uncontaminated diet whereas the effect of SC decreased in hens fed the AF contaminated diet. 4. The SC reduced some of the some adverse effects of AF, and improved functions of the non-specific immune system. Therefore, the SC extract which has been used for improving productive performance in birds and mammals may also be useful for modulating some of the effects of a low level, chronic dosage of AF.

[Non-small-cell carcinoma of the lung with invasive Aspergillus infection after chemotherapy]. / Sepsis und Aspergillose bei einer Patientin mit nicht-kleinzelligem Lungenkarzinom.

HISTORY: A 56-year-old woman had two years previously undergone a neck dissection and subsequent adjuvant radiotherapy for an adenocarcinoma at the base of the tongue (pT2NOMOG2) when a percutaneous endoscopic gastrostomy (PEG) catheter had been placed. She was now admitted for chemotherapy, recent onset of severe pain in the left hip and knee having been caused by metastasis of a non-small-cell lung carcinoma (NSCLC). She was cachectic and in a reduced general condition (Karnofsky index 80), but had recently only occasionally used the PEG catheter. There were no inflammatory changes of the skin at the site of the PEG. TREATMENT, COURSE AND OUTCOME: The first chemotherapy cycle was initially without complication, but after a week the patient's general condition deteriorated and she developed nausea, fever and pain around the markedly inflamed site of the PEG catheter insertion. Laboratory tests indicated severe neutropenia. Intensive antibiotic and antimycotic treatment at first brought about some improvement, but she died 11 days after admission. Necropsy revealed invasive aspergillosis, with the PEG as the portal of entry and spreading to the stomach and intestines, where numerous hyphae were identified. There had also been a disseminated intravascular coagulopathy. CONCLUSION: Bacterial infections (and occasionally, but difficult to diagnose, fungal infection) are quite common as a result of neutropenia during chemotherapy of solid tumors. Various risk factors, including reduced general condition and weight loss, must be individually assessed in the prevention or treatment of associated infectious complications in such cases.