Page 873 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 48 Antifungal Agents 859

levels is recommended in patients with serious invasive fungal
Iatrogenic Fungal Meningitis infections (especially mold infections); steady-state posaconazole
levels should be between 0.5 and 1.5 mcg/mL. Drug interactions
In September 2012, the U.S. Centers for Disease Control and with increased levels of CYP3A4 substrates such as tacrolimus and
Prevention (CDC) in Atlanta received reports of a number cyclosporine have been documented.
of cases of fungal meningitis in patients who had received Posaconazole is the broadest-spectrum member of the azole
injections with the corticosteroid methylprednisolone. An family, with activity against most species of Candida and
investigation revealed a multistate outbreak of septic arthritis, Aspergillus. It is the first azole with significant activity against
paraspinal infections, and meningitis due to environmental the agents of mucormycosis. It is currently licensed for salvage
molds, with the black mold Exserohilum rostratum being the therapy in invasive aspergillosis, as well as prophylaxis of fungal
most commonly isolated species. The outbreak was traced to infections during induction chemotherapy for leukemia, and
the injection of methylprednisolone that was contaminated for allogeneic bone marrow transplant patients with graft-versus-
during its preparation by a compounding pharmacy facility host disease.
in New England. Methylprednisolone injections are com-
monly given to patients with joint or back arthritis, and in
the affected cases the patients were not only inadvertently ISAVUCONAZOLE (ISAVUCONAZONIUM
injected with spores of environmental molds, but the nor- SULFATE)
mal immune response to this infection was inhibited by the
potent immunosuppressive effect of the corticosteroid. As of Isavuconazonium sulfate is a prodrug of the newest triazole, isa-
November 2013 more than 750 cases of fungal infection had vuconazole; 186 mg of the water-soluble prodrug is equivalent
been identified in 20 states, with over 60 deaths. Treatment of to 100 mg of isavuconazole. It is available as highly bioavail-
these infections was challenging, and the CDC recommended able oral capsules and an intravenous formulation. Following
the use of intravenous voriconazole as first-line therapy, with a 2-day loading dose of 372 mg administered every 8 hours,
the addition of liposomal amphotericin B in cases of severe isavuconazonium sulfate is given as a single 372-mg daily dose.
infection. Food does not significantly impact the oral absorption of isavu-
conazonium sulfate. Measurement of isavuconazole levels has
not been demonstrated to be of benefit. Coadministration with
strong 3A4 inhibitors (eg, ritonavir) or inducers (eg, rifampin)
Observed toxicities include rash and elevated hepatic enzymes. is not recommended.
Visual disturbances are common, occurring in up to 30% of Isavuconazole has an antifungal spectrum similar to that of
patients receiving intravenous voriconazole, and include blurring posaconazole. It is currently licensed for the treatment of invasive
and changes in color vision or brightness. These visual changes aspergillosis and invasive mucormycosis. Data from published
usually occur immediately after a dose of voriconazole and resolve clinical trials are limited. Preliminary evidence indicates that it is
within 30 minutes. Photosensitivity dermatitis is commonly better tolerated than voriconazole.
observed in patients receiving chronic oral therapy.
Voriconazole is similar to itraconazole in its spectrum of
action, having excellent activity against Candida sp (including ECHINOCANDINS
some fluconazole-resistant species such as Candida krusei) and
the dimorphic fungi. Voriconazole is less toxic than amphoteri- Chemistry & Pharmacokinetics
cin B and is the treatment of choice for invasive aspergillosis Echinocandins are the newest class of antifungal agents to be
and some environmental molds (see Box: Iatrogenic Fungal developed. They are large cyclic peptides linked to a long-chain
Meningitis). Measurement of voriconazole levels may predict fatty acid. Caspofungin, micafungin, and anidulafungin are
toxicity and clinical efficacy, especially in immunocompro- the only licensed agents in this category of antifungals, although
mised patients. Therapeutic trough levels should be between other drugs are under active investigation. These agents are active
1 and 5 mcg/mL. against Candida and Aspergillus, but not C neoformans or the
agents of zygomycosis and mucormycosis.
Echinocandins are available only in intravenous formulations.
POSACONAZOLE Caspofungin is administered as a single loading dose of 70 mg,
followed by a daily dose of 50 mg. Caspofungin is water soluble
Posaconazole was originally available only in a liquid oral formula- and highly protein-bound. The half-life is 9–11 hours, and the
tion and is used at a dosage of 800 mg/d, divided into two or four metabolites are excreted by the kidneys and gastrointestinal tract.
doses. Absorption is improved when taken with meals high in fat. Dosage adjustments are required only in the presence of severe
An intravenous form of posaconazole and a sustained acting tablet hepatic insufficiency. Micafungin displays similar properties with
form with higher bioavailability are now available. Posaconazole a half-life of 11–15 hours and is used at a dose of 150 mg/d for
is rapidly distributed to the tissues, resulting in high tissue levels treatment of esophageal candidiasis, 100 mg/d for treatment of
but relatively low blood levels. Measurement of posaconazole candidemia, and 50 mg/d for prophylaxis of fungal infections.