Combined High-Dose Caspofungin and Liposomal Amphotericin B for Treatment of Azole-Resistant Cerebral Aspergillosis

LETTER

The prevalence of azole-resistant aspergillosis is increasing and represents a public health issue in some countries, with an excess mortality of 25% (1). The advent of voriconazole improved the management of central nervous system (CNS) aspergillosis (2), but there is no consensual alternative in the case of azole resistance. We report the first case of successful treatment of CNS pan-azole-resistant aspergillosis.

A 79-year-old woman presented with right central facial palsy, hemiparesis, and aphasia. Her medical history included high blood pressure and ovarian adenocarcinoma treated by radical surgery followed by chemotherapy, and she achieved a complete response 2 months earlier.

Cerebral computed tomography revealed left cerebral infarctions with complete occlusion of the internal carotid artery by a mass with erosion of the carotid canal and the sphenoid bone wall. Subsequently, her neurological condition deteriorated with cranial nerve dysfunctions. In the absence of improvement, a transsphenoidal biopsy specimen of a lesion of the cavernous sinus revealed the presence of acute septate hyphae, and culture grew Aspergillus fumigatus sensu stricto. The fungal strain was identified using a polyphasic approach, including nucleotide sequencing and phenotypic characteristics. There was no extracerebral involvement.

Intravenous voriconazole (4 mg/kg every 12 h) combined with liposomal amphotericin B (L-amB) 5 mg/kg/day were administered. L-amB was then reduced to 3 mg/kg/d after 1 month due to mild kidney failure.

Despite antifungal treatment with close drug monitoring, the patient experienced seizure. Cerebral magnetic resonance imaging (MRI) revealed extension of the fungal lesion to the left prepontine cistern, causing mass effect on vascular structures (Fig. 1A and C).

FIG 1.

(A and C) Cerebral MRI axial T1-weighted imaging with gadolinium demonstrates complete occlusion of the left carotid artery, erosion of carotid canal and sphenoid bone wall by a tissular mass, and the extension to the left prepontine cistern with mass effect. (B and D) Cerebral MRI evaluation performed 3 years later displayed significant improvement, with complete regression of cerebral involvement.

Antifungal susceptibility testing using EUCAST methodology expressed as MICs revealed voriconazole, 2 mg/liter; isavuconazole, 4 mg/liter; itraconazole, 16 mg/liter; posaconazole, 0.5 mg/liter; amphotericin B, 0.125 mg/liter; caspofungin, 0.5 mg/liter; and micafungin, 0.007 mg/liter. Sequence analysis of the cyp51A gene revealed three amino acid substitutions, F46Y, M172V, and E427K. Voriconazole was then switched to caspofungin 100 mg/day in combination with L-amB. Caspofungin was increased to 150 mg/day as soon as L-amB dosage was reduced. After adaptation of antifungal therapy, the patient showed slow improvement in her condition. She remained in the hospital for 6 months. She was then discharged to the West Indies, her birthplace. We dispose of an imaging control performed 3 years later that confirms the successful outcome (Fig. 1B and D). She is currently alive 34 months after the diagnosis of aspergillosis, facing ovarian cancer relapse. She is able to walk; she did not experience any seizure.

We report the first isolation of a pan-azole-resistant A. fumigatus isolate harboring the mutation F46Y/M172V/E427K in the cyp51A gene, recovered from an azole-naive patient with CNS aspergillosis, with favorable outcome after 34 months of L-amB and high-dose caspofungin.

Since the 2000s, reports of azole resistance in A. fumigatus, resulting in therapeutic failure, have increased. Most resistance mutations are due to alterations on the cyp51A gene encoding sterol 14α-demethylase, an enzyme involved in cell membrane synthesis. Typical mutations are those combining a tandem repeat (TR) in the gene promoter and amino acid substitutions such as TR34/L98H or TR46/Y121F/T289A (3). Antifungal susceptibility testing of Aspergillus isolates is recommended in individuals with invasive aspergillosis except in triazole-naive patients in regions without resistance described in an epidemiologic surveillance program (4, 5). Our patient had no azole preexposure. She only reported travel in the Netherlands 4 years earlier.

Voriconazole is the recommended first-line therapy in CNS aspergillosis due to azole-susceptible isolates (2, 4). In the case of azole resistance, international experts may prefer L-amB at high doses, although its limited efficacy as single therapy has been emphasized (6). Combination therapy may be justified in this situation (5). Combined L-amB and high-dose caspofungin have proven effectiveness in murine models of CNS aspergillosis (7) and should be considered for pan-azole-resistant CNS aspergillosis (8).