What It’s Good For

Itraconazole remains a drug of choice for some dimorphic fungal infections, like histoplasmosis. It once had a larger role in the management and prophylaxis of aspergillosis and other mold infections, but it has been largely replaced by voriconazole. Itraconazole capsules are also used for the treatment of onychomycosis.

Don’t Forget!

Watch for those drug interactions, and be sure to counsel your patients on how to take their itraconazole formulation.

Voriconazole

The introduction of voriconazole represented a significant improvement in the treatment of mold infections. It is also a broad-spectrum antifungal like itraconazole, with good activity against Candida species and many molds. Unlike itraconazole, voriconazole is well absorbed and available in both highly bioavailable oral formulations and an IV admixture. Most importantly, voriconazole was shown to be superior to amphotericin B deoxycholate for invasive aspergillosis and has become the drug of choice for that disease. With widespread use, however, limitations in terms of highly variable pharmacokinetics and long-term adverse effects have emerged.

Mechanism of Action

All azoles inhibit fungal cytochrome P450 14-alpha demethylase, inhibiting the conversion of lanosterol into ergosterol, which is a component of the fungal cell membrane.

Spectrum

Good: Candida albicans, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Candida krusei, Cryptococcus neoformans, Aspergillus species, many other molds

Moderate: Candida glabrata, Candida albicans that are fluconazoleresistant, Fusarium species

Poor: Mucorales

Adverse Effects

In addition to the hepatotoxicity, rash, and drug interactions that are common with this class, voriconazole has some agent-specific adverse effects worth watching.

Renal: The cyclodextrin solubilizer that intravenous voriconazole comes in is known to accumulate in renal dysfunction. This vehicle is thought to be nephrotoxic, but it is almost certainly less nephrotoxic that amphotericin B, so the use of intravenous voriconazole with renally insufficient patients is a risk/reward equation that should be considered with each patient.

Visual effects: Visual effects such as seeing wavy lines or halos around bright lights are very common and dose-related; they tend to go away with continued use.

Central nervous system effects: Distinct from the common visual effects of voriconazole, patients sometimes experience visual and auditory hallucinations. These effects are not permanent and tend to occur at higher voriconazole levels (especially during peak concentration periods).

Dermatologic: Voriconazole has long been known to cause sun sensitivity and patients should be advised to use sunscreen and avoid excessive sun exposure. Because voriconazole has been shown to be so useful for treating and preventing fungal infections, it has been used for durations far exceeding those studied in clinical trials. However, some studies now suggest an association between prolonged voriconazole use and certain skin cancers. Thus, it is even more essential to counsel patients on reducing sun exposure if they are taking voriconazole

Dosing Issues

Voriconazole has highly variable interpatient pharmacokinetics and nonlinear elimination, making it difficult to dose correctly. If you are committing your patient to an extended course of therapy for voriconazole, the standard of care has become to monitor serum drug concentrations (usually a trough level). There is no official consensus, but trough concentrations in the range of 2–5 mg/L are usually considered to be in the therapeutic window.

Important Facts

Voriconazole is active against some fluconazole-resistant strains of

Candida albicans, but it is less active against them than fluconazolesusceptible strains. An echinocandin is a better choice, but consider susceptibility testing if you need to use voriconazole for an oral option.

Voriconazole is a potent inhibitor and a substrate of the cytochrome P450 system. The list of drugs that interact with voriconazole is long and varied. Some of them are contraindicated, such as rifampin, while others, such as calcineurin inhibitors (e.g., cyclosporine) require dose adjustments. This is significant because many of the patients who require voriconazole are immunosuppressed.

The IV form of voriconazole contains a cyclodextrin vehicle that accumulates in renal dysfunction and may be nephrotoxic. It is contraindicated with a creatinine clearance of less than 50 ml/min. The oral formulations avoid this issue.

Voriconazole is eliminated hepatically and is unlikely to be useful in the treatment of candiduria.

What It’s Good For

Voriconazole is a drug of choice for invasive aspergillosis and is frequently used in the treatment of infections caused by other molds. It can be used for candidiasis as well, but fluconazole and echinocandins are more frequently used for these infections. Some clinicians use voriconazole in the empiric treatment of febrile neutropenia.

Don’t Forget!

Watch for drug interactions with voriconazole, and consider checking drug concentrations if you are using it for an extended course of therapy.

Posaconazole

Posaconazole is an analog of itraconazole that is substantially more active against many fungi. Currently, it is indicated only for the prophylaxis of fungal infections patients and the treatment of oropharyngeal candidiasis. It was the first azole with good activity against Mucorales, a difficult-to-treat order of molds that most antifungals (voriconazole included) do not treat; however, the

recently approved isavuconazole also has activity against these pathogens (see next section).

Mechanism of Action

All azoles inhibit fungal cytochrome P450 14-alpha demethylase, inhibiting the conversion of lanosterol into ergosterol, which is a component of the fungal cell membrane.

Spectrum

Good: Candida albicans, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Candida krusei, Aspergillus species, Mucorales, many other molds, dimorphic fungi

Moderate: Fusarium species, Candida glabrata

Though posaconazole is active against these organisms, comparative clinical trial data are lacking for many of them.

Adverse Reactions

Posaconazole seems to be well tolerated, though it can cause hepatotoxicity, nausea, and rash. It has a similar propensity to cause drug interactions via cytochrome P450 as the other azoles.

Dosing Issues

A key limitation to posaconazole’s use was its initial availability only as an oral suspension. This formulation requires administration with food to increase its absorption; foods with a high fat concentration, nutritional supplements containing fat, and low-pH beverages like soda all increase absorption. Even under the best circumstances, absorption of the suspension is limited and variable. Recently a delayed-release tablet formulation has been approved that achieves much higher and more reliable concentrations. Note, however, that the tablet cannot be crushed or chewed. There is also an IV formulation.