What is the significance of breakthrough infection with isavuconazole (Cresemba)?

From the Guidelines

Breakthrough isavuconazole is a viable treatment option for patients who have failed or cannot tolerate first-line antifungal therapies, particularly for invasive aspergillosis and mucormycosis. For breakthrough infections, isavuconazole is typically administered with a loading dose of 200 mg every 8 hours for 6 doses (48 hours), followed by a maintenance dose of 200 mg once daily 1. The medication is available in both oral and intravenous formulations, allowing for flexible administration. Isavuconazole is particularly useful for invasive aspergillosis and mucormycosis that have not responded to other antifungals like voriconazole or posaconazole. It offers advantages including better tolerability, fewer drug interactions, no need for therapeutic drug monitoring, and no dose adjustments for renal impairment. The drug works by inhibiting the synthesis of ergosterol, an essential component of fungal cell membranes, thereby disrupting membrane integrity and causing fungal cell death. Common side effects include nausea, vomiting, diarrhea, and elevated liver enzymes, but it generally has a more favorable side effect profile compared to other triazole antifungals. Key considerations for the use of isavuconazole in breakthrough infections include:

• Its efficacy in treating mucormycosis, with similar results to amphotericin B formulations 1
• Its potential to be used as a first-line treatment for mucormycosis, with a more favorable side effect profile compared to other antifungals
• The importance of monitoring for potential side effects, such as shortened QTc interval, and adjusting treatment as needed. In the context of breakthrough infections, the management of suspected or documented breakthrough invasive pulmonary aspergillosis (IPA) in the context of mold-active azole prophylaxis or empiric suppressive therapy is not defined by clinical trial data, but a switch to another drug class is suggested 1. Therefore, isavuconazole is a reasonable choice for breakthrough infections, particularly in patients who have failed or cannot tolerate first-line therapies.

From the Research

Breakthrough Invasive Fungal Infections on Isavuconazole

• Breakthrough invasive fungal infections (bIFIs) have been reported in patients receiving isavuconazole prophylaxis, with an incidence of 17.9% in one study 2.
• The most common causes of bIFIs in patients receiving isavuconazole prophylaxis were Fusarium, Candida, Mucorales, and Aspergillus 2.
• Isavuconazole serum concentrations were comparable to industry-sponsored clinical trials in patients who developed bIFIs, suggesting that the breakthrough infections were not due to subtherapeutic drug levels 2.
• All-cause mortality among patients who developed bIFIs on isavuconazole prophylaxis was 47.4% 2.

Risk Factors for Breakthrough Invasive Fungal Infections

• Neutropenia was a significant risk factor for the development of bIFIs in patients receiving isavuconazole prophylaxis, with 12 patients being neutropenic for a median of 28 days prior to bIFI diagnosis 2.
• Clinically significant cytomegalovirus co-infection was noted in 5.3% of patients who developed bIFIs on isavuconazole prophylaxis 2.
• There were no significant differences in baseline comorbidities and potential risk factors between patients who developed bIFIs and those who did not 2.

Efficacy of Isavuconazole in Preventing Breakthrough Invasive Fungal Infections

• Isavuconazole has been shown to be effective in preventing invasive fungal infections in immunocompromised patients, with a breakthrough rate of 8.5% in one study 3.
• The efficacy of isavuconazole in preventing bIFIs is comparable to that of other antifungal agents, such as posaconazole and voriconazole 3.
• Isavuconazole has a favorable safety profile and is well-tolerated, making it a promising alternative for prophylaxis and treatment of invasive fungal disease 3, 4.