Isavuconazole was first approved by the U.S. Food and Drug Administration in March 2015. It is a broad spectrum antifungal which works in the same way as the other azole antifungals by inhibiting cytochrome P450 (CYP)-dependent 14-alpha-lanosterol demethylation (what a mouthful!), thereby interfering with fungal cell wall synthesis. This allows ergosterol toxic molecules to build up inside the cytoplasm which eventually kills the fungus. Isavuconazole is able to affect a broader range of fungi than other azoles because it has greater affinity for binding to CYP.
What is the spectrum of activity of Isavuconazole?
Isavuconazole is active against almost all yeasts including Candida albicans, C. parapsilosis and C. lusitaniae as well as species often resistant to azoles such as C. krusei and many C. glabrata. However there are some C. glabrata resistant to Isavuconazole so individual drug sensitivity testing would be required before it was used. Isavuconazole is also active against more uncommon yeasts such as Cryptococcus neoformans and Cryptococcus gattii (which can cause cryptococcal meningitis in immunosuppressed patients) as well as the weird and wonderful yeasts such as Trichopsoron spp., Geotrichum capitatum, Rhodoturula spp. and even baker’s yeast, Saccharomyces cerevisiae.
Most of the medically important moulds are sensitive to Isavuconazole including Aspergillus spp., and the zycomycetes (the cause of the invasive fungal infections known as mucormycosis). Some other weirder moulds are also sensitive to Isavuconazole such as Scedosporium apiospermum. However Fusarium spp. are resistant; which is rather disappointing as it was to be the focus of this blog!! But I’ll continue on my Isavuconazole learning curve otherwise this will be a very short blog.
Isavuconazole has shown activity against dimorphic fungi (which can be yeasts and moulds depending on temperature) but the number of isolates tested has been very small. Dimorphic fungi are an odd group of fungi which exist as yeasts at body temperature but at lower environmental temperatures they grow as moulds. Examples include Histoplasma capsulatum, Coccidiodes imitis and Blastomyces dermatitidis.
How is Isavuconazole administered?
Isavuconazole is actually given as a prodrug, Isavuconazonium sulfate, which is broken down to the active form in the blood stream. The active drug is then rapidly distributed to tissues so that it becomes undetectable in the blood stream within about 30 minutes of an IV infusion and 2-3 hours following oral administration.
Isavuconazole is available as both intravenous and oral formulations. In fact Isavuconazole is 98% orally bioavailable (even when given with food) which means there is rarely any need to give it IV routinely. This is great. Also its behaviour is pretty consistent between different people, which makes it easy to manage, as levels will be predictable.
Isavuconazole is metabolised and inactivated in the liver however it is not yet known how it is removed from the body. For example, it is not eliminated in urine (as most drugs are) and therefore it would be no good to treat a urinary fungal problem. In animal studies it has been found in faeces even after IV administration so it is expected that this is the probable route of elimination (but how it gets there no one yet knows!).
Although it is hepatically metabolised there is no need to reduce the dose in mild to moderate liver failure (there is no data for severe liver failure, so Isavuconazole is probably best avoided in severe liver failure). As Isavuconazole is not excreted through the kidneys there is no need to dose adjust in renal failure. At present Isavuconazole is contraindicated in pregnancy and breast feeding because there is no data to say it is safe.
The normal adult dose of Isavuconazole is a loading dose of 200mg TDS for two days then 200mg OD (cost averaged out over 10 days is £60/day – i.e. 14 tablets £600).
Does Isavuconazole interact with other medications?
One of the main drawbacks to the azole antifungals is their habit of interacting with other drugs. For Isavuconazole the main interactions are:
- Increased Isavuconazole levels with Lopinavir/ritonavir (HIV medications)
- Decreased Isavuconazole levels with Rifampicin, Carbamazepine, long-acting barbiturates and St. John’s Wort (often found in many herbal remedies)
- Increased drug levels of Sirolimus, Tacromlimus, Cyclosporin, Mycophenolate mofetil, Colchicine, Dabigatran (an anticoagulant) when given with Isavuconazole
- Decreased drug levels of Lopinavir/ritonavir when given with Isavuconazole
Overall the interactions with Isavuconazole are much less than with comparable azole antifungals such as Posaconazole and Voriconazole.
What are the side effects of Isavuconazole?
The most common side effects of Isavuconazole are:
- Nausea, vomiting and diarrhoea
- Abnormal liver function tests, mainly increased alanine aminotransferase (ALT) and alkaline phosphatase (ALP)
- Shortened QT interval on electrocardiogram (ECG) in relation to heart electrical conduction – this sounds alarming but so far the clinical significance of this in patients with a previously normal QT interval is unknown and it may not be of concern.
In general, yet again, the side effects of Isavuconazole appear to be less than with Posaconazole and definitely less than Voriconazole which has nasty side effects (as above plus visual disturbance, bone marrow suppression and hepatotoxicity amongst many others) in about 30% of patients who take it.
What are the clinical uses of Isavuconazole?
Isavuconazole has been approved for the treatment of invasive aspergillosis and mucormycosis.
In a double-blind, randomised controlled trial against Voriconazole (the current gold standard) for the treatment of invasive aspergillosis, Isavuconazole was shown to be non-inferior. There were 231 patients in the study and the 42 day mortality and the clinical response was even slightly better for Isavuconazole although this wasn’t statistically significant. In a more open study into the treatment of mucormycosis (where cases are so rare that big randomised and blinded studies are not possible) Isavuconazole was shown to be as good as Amphotericin B or Posaconazole which are the current mainstays of treatment. Although “as good as” and “non-inferior” may not sound too exciting, its reduced side effects, oral bioavailability and low cost are in Isavuconazoles favour. Approximate cost comparison: Isavuconazole cost for 10 days is £600, Voriconazole cost for 10 days is £860, Posaconazole cost for 10 days is £995, Amphotericin B cost for 10 days is a whopping £6,768!!!
In terms of fusarium infections treated with Isavuconazole there appear to be only 9 patients presented as case reports in the literature. Of these, only 3 (33%) had complete or partial resolution of their infection, whereas in 6 it made no difference at all. That’s not great…as conventional treatment with Voriconazole results in up to 50% success.
So the current recommendations are to use Isavuconazole in patients who are intolerant to, or fail treatment with, normal first line therapies for invasive aspergillosis or mucormycosis. However it may only be a short time before Isavuconazole becomes the normal first line treatment in these infections. But for fusarium keratitis which was what first got me looking into Isavuconazole, it appears that this isn’t going to be the cure after all….