Cerebral aspergillosis (CA) is a lethal invasive fungal infection, with current national and international guidelines recommending voriconazole as the first-line antifungal treatment. While newer triazoles, such as isavuconazole, demonstrate good blood-brain barrier penetration, there is still limited clinical evidence to confirm their efficacy and safety for treating CA. Recently, Clinical Infectious Diseases published a retrospective study led by the European Fungal Infection Study Group (EFISG) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). The study highlights that isavuconazole is well-tolerated in the treatment of CA, with mortality rates comparable to those of voriconazole.

Cerebral aspergillosis (CA) is a rare but deadly form of invasive aspergillosis (IA), predominantly affecting immunocompromised individuals. The blood-brain barrier limits the effectiveness of most antifungal medications in the central nervous system (CNS), leading to poor prognosis for CA patients. Current guidelines recommend voriconazole as the first-line treatment for CA. However, its toxicity and potential drug interactions necessitate alternative treatment options.

The EFISG study, a European multicenter retrospective analysis, examined 40 confirmed or clinically diagnosed CA cases treated with isavuconazole between 2014 and 2022 across 10 European countries. The patients included 53% with hematological malignancies and 20% organ transplant recipients. The study’s primary outcome was the 12-week overall survival rate following isavuconazole treatment, which was compared to a weighted control group from the previously published French CEREALS cohort.

Key findings included:

• Of the 10 patients treated with isavuconazole as first-line therapy, 70% achieved CA control.
• Thirty patients received isavuconazole as a second-line therapy, with a median delay of 65 days after the initial treatment due to drug-related adverse effects (50%) or treatment failure (23%). The CA control rate for isavuconazole monotherapy was 73%.
• Seventeen patients (43%) underwent neurosurgery.
• Isavuconazole concentrations were low in cerebrospinal fluid (CSF) but high in serum and brain tissue.
• Treatment discontinuation due to isavuconazole toxicity occurred in 7.5% of patients, with a 12-week mortality rate of 18%.
• Survival rates were comparable between patients treated with isavuconazole and those treated with voriconazole in the CEREALS cohort.

The results of the EFISG study indicate that isavuconazole is a well-tolerated treatment option for CA. Mortality rates for patients treated with isavuconazole were similar to those reported for voriconazole. Despite low CSF concentrations, isavuconazole showed efficacy, likely due to sufficient levels in serum and brain tissue. For CA forms primarily involving the meninges, future studies are needed to evaluate the drug’s efficacy in this context. Additionally, although the sample size was small, the study showed that isavuconazole is safe for use in pediatric populations.

Cerebral aspergillosis (CA), also known as intracranial aspergillosis (ICA), is an invasive fungal infection that affects intracranial structures, including brain parenchyma, meninges (mainly the dura), brain vasculature, and the cavernous sinus. CA predominantly occurs in immunosuppressed individuals, such as those with malignancies, AIDS, organ transplants, or those on prolonged corticosteroid or immunosuppressant therapy. Aspergillus fumigatus is the most common pathogen causing CA, followed by Aspergillus flavus and Aspergillus terreus.

Guidelines currently recommend voriconazole as the first-line treatment for CA. For patients who cannot tolerate voriconazole due to adverse drug reactions, isavuconazole, posaconazole, or liposomal amphotericin B are considered alternatives.

Isavuconazole is a new triazole antifungal that inhibits 14-α-sterol demethylase, blocking ergosterol synthesis and promoting fungal cell apoptosis. In animal studies, the brain tissue-to-plasma concentration ratio of isavuconazole ranges from 1 to 1.7. In clinical reports, brain tissue concentrations on the fourth day of administration reached 1.46 mg/kg, with an estimated brain tissue/plasma concentration ratio of 0.9, which is higher than the susceptibility thresholds for Aspergillus fumigatus and Aspergillus flavus. Due to its good CNS penetration, the 2021 guidelines from the American Society for Transplantation and Cellular Therapy (ASTCT) recommended isavuconazole and voriconazole as the best treatments for CNS-invasive aspergillosis.

A retrospective study by Schwartz et al. on 36 cases of CNS-invasive mucormycosis treated with isavuconazole, including cases of mucormycosis, aspergillosis, and cryptococcosis, showed overall survival rates of 80.6% and 69.4% at 42 and 84 days, respectively. Clinical efficacy at the end of treatment was 58.3%.

The French CEREALS cohort study, which included 113 CA patients (88 treated with voriconazole monotherapy or combination therapy, 22 with liposomal amphotericin B, and others with caspofungin or unknown agents), reported 6-week, 3-month, and 1-year mortality rates of 45%, 51%, and 63%, respectively. Notably, in the EFISG study, isavuconazole was more frequently used in combination therapy (70%) as first-line treatment, compared to 44% for voriconazole in the CEREALS cohort.

While both monotherapy and combination therapy with isavuconazole as a first-line treatment did not show increased mortality or disease progression risks, the authors attributed this to the small number of cases and differences in patient inclusion periods (CEREALS: 2006-2018; EFISG: 2014-2022). As a second-line treatment, isavuconazole’s patient outcomes were not significantly different from other drugs. Compared to other antifungal medications, isavuconazole offers advantages in safety and reduced drug interactions, with a 5% discontinuation rate due to adverse drug effects, compared to 15% in the CEREALS study for voriconazole.