Posaconazole

Posaconazole is an analog of itraconazole that is substantially more active against many fungi. 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 the next section). Recently posaconazole was shown to be noninferior to voriconazole in the treatment of invasive aspergillosis.

Adverse Reactions

Posaconazole carries similar risks of hepatotoxicity and QT prolongation as other azoles but lacks the sensory or cutaneous side effects of voriconazole. While it is a perpetrator of drug interactions via its strong inhibition of CYP 3A4, it is not a CYP substrate itself and so is slightly less likely to be a drug interaction problem. However, its inhibition of enzymes involved in steroid metabolism has led to cases of hypertension and hypokalemia as a component of posaconazole-induced pseudohyperaldosteronism.

Important Facts

• Posaconazole’s most common use has been in the prophylaxis of fungal infections in high-risk patients. As with voriconazole, many of these patients are taking immunosuppressants that interact with posaconazole, so keep close tabs on those drug concentrations.
• The in vitro activity of posaconazole against Aspergillus is generally similar to that of voriconazole. Previously, a lack of clinical trial data comparing posaconazole to voriconazole relegated it to second-line use, but with the publication of recent study showing similar outcomes in invasive aspergillosis, posaconazole may become a first-line agent.
• Although its pharmacokinetics are less variable than voriconazole’s, assays for posaconazole drug concentrations are available and their measurement should be considered for patients with questionable absorption, or if posaconazole is being used for treatment of invasive infections.

What It’s Good For

Posaconazole is most commonly used as prophylaxis against fungal infections in susceptible hosts, but it also plays a key role in the management of mucormycosis and may see increasing use in treatment of invasive aspergillosis. It is used as an alternative in oropharyngeal candidiasis and fungal infections refractory to other agents.

Don’t Forget!

As with itraconazole, it is vitally important to take into account which formulation your patient is taking and dose and administer accordingly.

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.

• Good: Aspergillus species, Mucorales, many other molds, dimorphic fungi, most Candida spp
• Moderate: Fusarium species, C glabrata

As with itraconazole, there are multiple oral preparations with important differences between them. The oral suspension formulation was the first FDA-approved preparation and requires administration with food to increase its absorption (Table 31-1); 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. Subsequently a delayed-release tablet formulation has been approved that achieves much higher and more reliable concentrations. There is also an IV formulation that contains a cyclodextrin solubilizer; as with the IV voriconazole preparation, administration of the IV form to patients with renal failure is a risk/benefit decision (which almost always comes down in favor of giving the IV posaconazole).