https://orcid.org/0009-0004-0959-6493
Abstract
Acute invasive fungal rhinosinusitis represents a severe, life-threatening condition that necessitates prompt diagnosis and intervention. In this case report, we discuss the use of isavuconazole, a novel, broad-spectrum triazole antifungal, approved for use in Canada in 2019 (Government of Canada. Summary Basis of Decision – Cresemba – Health Canada. Summary Basis of Decision. 2019. Accessed 6 June 2024. https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00424#:~:text=Summary%20Basis%20of%20Decision%20(SBD)%20for%20Cresemba&text=Summary%20Basis%20of%20Decision%20(SBD)%20documents%20provide%20information%20related%20to,original%20authorization%20of%20a%20product) that can be considered an alternative to voriconazole.
We present the case of a 78-year-old man with a unique case of invasive Aspergillus rhinosinusitis and orbital aspergillosis. He was admitted for urgent left maxillary antrostomy, left anterior and posterior ethmoidectomy, and left transorbital resection of lesion tissue with orbital decompression. His treatment course was complicated by a contraindication to voriconazole because of prolonged QTc interval and inability to tolerate IV amphotericin B.
The patient was treated with a 14-week course of isavuconazole as an alternative to voriconazole. At 3 months, there was no clinical evidence for infection, and the patient was sent for a computed tomography (CT) of the head and sinus to assess for evidence of active infection or bone destruction, which showed significant improvement in paranasal sinus inflammation and soft tissue infiltration. At his 6-month follow-up, his CT head showed regression in inflammatory change, with no deterioration in his sinusitis, and no further antifungal treatment was required.
Given the novelty of isavuconazole, there has been limited experience with its use in the setting of rhinosinusitis and orbital invasive aspergillosis. This case highlights isavuconazole as a reasonable alternative to voriconazole and other triazoles in patients that are intolerant or have contraindications related to QTc prolongation.
Case review
This review aims to share our experience in using isavuconazole for the management of invasive aspergillus rhinosinusitis and orbital aspergillosis. Isavuconazole would be considered a reasonable alternative to voriconazole in patients who are intolerant to voriconazole or have contraindications related to corrected QT interval (QTc) prolongation. While isavuconazole is non-inferior to voriconazole [1] and has more favorable tolerability [2], a significant barrier to the routine use of isavuconazole over voriconazole is the cost. According to the Canadian Agency for Drugs and Technologies in Health’s (CADTH) pharmacoeconomic review report, an 8-week course of oral isavuconazole is compared to an equivalent 8-week course of oral voriconzole. A treatment course with isavuconazole is approximately six times the price of an equivalent voriconazole treatment course [3]. The significant cost difference may be attributed to the availability of generic voriconazole in Canada while isavuconazole, at this time, remains a brand name product only.
A 78-year-old man with a history of type 2 diabetes mellitus, hypertension, dyslipidemia, and atrial fibrillation presented to his local emergency department with left facial pain and sinus pressure. Pertinent home medications included apixaban 5 mg twice daily, furosemide 40 mg daily, perindopril 8 mg daily, and empagliflozin 25 mg daily. After 6 weeks of symptoms, he awoke with significant vision loss in the left eye, seeing just a ring of peripheral light around a central scotoma. Vision loss progressed over approximately 10 days to the point of not being able to perceive light. On examination at this time, visual acuity was 20/20 in the right eye, but no light perception in the left. The left pupil was mid-dilated and minimally reactive with a left relative afferent pupillary defect. There was complete horizontal ophthalmoplegia and minimal vertical movement of the left eye, and 6 mm of proptosis. Lingua nigra was also present. CT head and sinus showed probable left maxillary fungal sinusitis with concerns for direct spread in the orbit and pterygopalatine fossa with involvement of adjacent inferior aspect of left orbit with associated orbital mass effect in proptosis (Figures 1 and 2). This case presented with findings consistent with a mycetoma (Figure 3), but also with fat stranding and soft tissue thickening in the pterygopalatine fossa and orbit (Figures 4 and 5). He was admitted and immediately consented for emergent endoscopic sinus surgery with biopsy and decompression of the left orbit with frozen sections for histologic confirmation of fungal elements and angioinvasion.
Coronal CT sinus showing mycetoma (arrow).
Coronal CT sinus showing atypical soft tissue in posterior orbit (arrow).
Endoscopic image of mycetoma material removed from maxillary sinus (arrow).
Endoscopic image of posterior wall maxillary sinus mucosa after removal of mycetoma (arrow).
Endoscopic image of posterior orbital biopsy site that confirmed invasive fungal disease (arrow).
Intra-operative pathology reports showed left orbital biopsy positive for fragmented fungal hyphae and left posterior ethmoid positive for fungal hyphae, favoring Aspergillus species. Frozen sections collected intra-operatively showed Aspergillus on some sections but no frank angioinvasion. Empiric amphotericin B liposomal 380 mg (4.5 mg/kg) IV every 24 hours was started immediately, along with piperacillin-tazobactam 4.5 g IV every 6 hours. Tissue cultures later reported positive for Aspergillus fumigatus, Pseudomonas aeruginosa, and Staphylococcus lugdunensis. After three doses of amphotericin B liposomal, the patient became severely hypokalemic (serum potassium = 2.6 mmol/L). Furosemide was put on hold, and despite frequent routine IV and oral potassium chloride replacement, the serum potassium remained persistently low. Oral voriconazole was not considered a safe alternative to amphotericin B due to a prolonged QTc of 521 ms on electrocardiogram (ECG). Therefore, the patient was started on oral isavuconazole 200 mg every 8 hours for 6 doses, followed by 200 mg oral daily. The patient completed a concurrent course of piperacillin-tazobactam for 4 weeks and was discharged on oral isavuconazole 200 mg daily for the next 14 weeks. After 14 weeks of isavuconazole therapy, the patient was seen in follow-up and had no symptoms of sinusitis, no fever, no nasal discharge, and no facial pain or pressure. Proptosis was reduced to 4 mm, but there was no improvement in vision, extraocular movements, or corneal sensation of the left eye. Follow-up CT showed regression in the inflammatory disease and no worsening of the sinusitis. At the patient’s 6-month follow-up with infectious diseases, his only symptom was persistent vision loss, and no further antifungal treatment was required.
Invasive aspergillus rhinosinusitis with orbital aspergillosis represents a rare but critical manifestation of fungal infection. The case presentation was not as an “acute invasive fungal sinusitis” but rather a “chronic invasive fungal sinusitis.” As a chronic invasive fungal rhinosinusitis, the endoscopic findings were underwhelming. There was not eschar or necrotic tissue and the mucosa in the sinuses looked otherwise like a regular rhinosinusitis case. The aggressive nature of the infection can lead to rapid tissue necrosis, extending beyond the sinuses to involve the central nervous system, if not promptly addressed [4]. It was only on histopathology that the diagnosis of chronic invasive fungal rhinosinusitis could be made.
Voriconazole is the triazole of choice and has been shown to be superior to amphotericin B (AmB) in the primary treatment of invasive aspergillosis [5]. The Infectious Diseases Society of America (IDSA) currently recommends amphotericin B and its lipid derivatives as an appropriate initial treatment option in settings where voriconazole cannot be administered [6]. However, for patients who experience significant side effects, alternative antifungal options are limited. Isavuconazole is a novel, broad-spectrum triazole antifungal, approved for use in Canada in 2019 [7] that can be considered an alternative.
The SECURE trial demonstrated isavuconazole was non-inferior to voriconazole in patients suspected of having invasive aspergillosis [1]. However, the SECURE trial was powered to only demonstrate non-inferiority and, given the rarity of invasive aspergillus rhinosinusitis and orbital aspergillosis, no other randomized control trials currently exist supporting treatment with isavuconzole in this patient population. Case studies in immune-compromised patients (i.e. AIDS, active malignancy) with mucormycosis have demonstrated the success of isavuconazole use. To our knowledge, we report the first case of isavuconazole treatment for invasive aspergillus rhinosinusitis expanding to orbital aspergillosis [8]. This case highlights the effectiveness of isavuconazole as an alternative triazole for invasive aspergillosis, particularly in patients with contraindications or intolerance to voriconazole and AmB. Unfortunately, despite the successful treatment of the patient’s fungal rhinosinusitis, due to the delayed initiation of antifungal therapy in relation to onset of vision loss, vision function of the patient’s left eye could not be restored.
Upon discontinuation of AmB due to hypokalemia, voriconazole was initially considered for the patient. Ultimately, isavuconazole was chosen over voriconazole given the patient’s QTc interval and drug interactions with the patient’s anticoagulation therapy. QTc prolongation, a class-wide effect of triazoles, often poses a major obstacle to therapy [9]. In contrast to others within its class, isavuconazole can lead to dose-dependent QTc shortening, allowing for triazole therapy despite concerns for a prolonged QTc [10]. Furthermore, the safety profile and incidence of adverse events related to isavuconazole is much lower, making it more tolerable compared to others within the triazole class [2]. This translates to lower incidence of drug discontinuation and ultimately more favorable treatment outcomes.
Similar to others within its class, isavuconazole is a substrate for CYP3A4 and is also a moderate inhibitor of CYP3A4. Comparatively, voriconazole and posaconazole are considered strong CYP3A4 inhibitors, which poses more significant drug interactions in comparison to isavuconazole [9]. The Canadian product monograph for apixaban indicates that concomitant use with a strong CYP3A4 inhibitor is contraindicated (i.e. voriconazole). Acknowledging that isavuconazole is a moderate inhibitor of CYP3A4 and could still impact the metabolism of the patient’s apixaban, the patient was referred to the local anticoagulation clinic for ongoing management. Further studies are warranted to elucidate its specific role in different patient populations and clinical scenarios. By sharing this case, we aim to contribute valuable insights into the effective use of isavuconazole and underline the importance of timely intervention in improving patient outcomes.
Author contributions
A.T.: gathering data, writing the article; L.S., L.B.: involved in the patient case as initial consult, providing context, critical review; and R.R.: involved in the patient case as initial consult, providing context, critical review, final approval, and analyzing data.
Conflict of interest
A.T.: AVIR Pharma to provide reimbursement for a portion of costs associated with the successful publication of this manuscript. The remaining author(s) declare that there are no conflicts of interest.
Funding
The generation of this case received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. A portion of costs associated with the successful publication of manuscript was paid by AVIR Pharma.
Data availability
Data access statement: Authors had complete access to data and continue to have ongoing access to data as a subject of the case is still an active patient. The data underlying this article cannot be shared publicly for the privacy of the individual in this case. The data will be shared on reasonable request to the corresponding author.
