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650 PART 5: Infectious Disorders

TABLE 70-7 Characteristics of Echinocandins Used in the ICU
Anidulafungin Caspofungin Micafungin
Formulation IV IV IV
Dosages 200 mg loading dose, then 100 mg daily 70 mg loading dose, then 50 mg daily 100 mg daily; no loading dose needed
Protein binding (%) 84 97 99
Distribution (L/kg) 0.7-0.9 N/A 0.24
Half-life (h) 24-26 9-11 11-17
Substrate/inhibitor of CYP450 No Poor substrate/weak inhibitor Poor substrate/weak inhibitor
Metabolism Chemical degradation in serum Hepatic peptide hydrolysis and N-acetylation Hepatic arylsulfatase and catechol-O-methyltrans-
ferase
Elimination Feces; <1% in urine 35% in feces, 41% in urine (1% active drug) 40% in feces, 15% in urine (<1% active drug)
CSF penetration Low Low Low
Dosage adjustment in renal impairment None None None
Dosage adjustment in hepatic impairment None Child-Pugh <7: none; Child-Pugh 7-9: 35 mg Child-Pugh ≤9: none; Child-Pugh >9: no data
after 70 mg loading dose; Child-Pugh >9: no data
CSF, cerebrospinal fluid; IV, intravenous.
Adapted from References 104 and 105.

Voriconazole can cause hepatotoxicity, as can other azoles, and has share many similarities, but do have pharmacological differences
105
also several unique adverse effects. These include photosensitivity, (Table 70-7). The spectrum of activity of all three is similar, and the
generally not a problem for ICU patients, and visual changes, including IDSA Guidelines consider all three equivalent in efficacy. Most hos-
82
blurry vision, wavy lines, and flashes of light that occur about a half hour pitals select only one agent for their formulary, a decision often based
after administration and usually resolve within an hour. They have no on cost considerations.
lasting effect on the retina. Separate from these ocular effects, high The echinocandins are only available as intravenous formulations.
102
serum levels of voriconazole are associated with visual hallucinations The half-life is long, and once daily dosing is appropriate. They are large
and other central nervous system toxicities. It is recommended that all molecules that are highly protein bound and distribute poorly into the
103
patients treated with voriconazole have serum levels measured to ensure cerebrospinal fluid and the eye. They are not excreted as active drug
105
that adequate levels (>1 µg/mL) are achieved for efficacy and to prevent into the urine. The dosing of each of the echinocandins is noted in
toxicity associated with levels >5.5 µg/mL. 103 Table 70-7.
Itraconazole does not have a role for treating invasive candidiasis, Among all the antifungal drug classes, echinocandins appear to have
and there are no studies assessing the efficacy of posaconazole for this the fewest side effects. This can be attributed to two factors. They
106
indication. Both of these agents are available only as oral formulations interfere with synthesis of the fungal cell wall, a structure not shared
and absorption issues are problematic, so they cannot be relied on in with mammalian cells. They are also not metabolized through the CYP
the ICU setting. 450 system, but rather are broken down in the liver (micafungin and
Echinocandins: The echinocandins are fungicidal for most Candida caspofungin) or the blood (anidulafungin), and thus, drug-drug interac-
species, which contrasts with the azoles, which are fungistatic for tions are few. They can cause phlebitis when given through a peripheral
Candida. The exception is C parapsilosis, for which the echinocan- vein; hypokalemia and hepatotoxicity have been reported, but the latter
dins are less active than the azoles. The three echinocandin agents has not been clearly defined.
104

TABLE 70-8 Characteristics of Formulations of Amphotericin B Used in the ICU
Category Amphotericin B deoxycholate Amphotericin B lipid complex; Amphotericin B colloidal disper- Liposomal amphotericin B;
ABLC; Abelcet sion; ABCD; Amphotec, Amphocil AmBisome
Formulation Micelle Ribbons/sheets Lipid disk Unilamellar vesicles
IV infusion IV infusion IV infusion IV infusion
Size (nm) <10 1600-11000 122(±48) 80-120
Dosage and rate of infusion 0.7-1 mg/kg daily infuse over 4 h 5 mg/kg daily infuse over 2 h 3-6 mg/kg daily infuse over 2 h 3-5 mg/kg daily infuse over 2 h
Peak serum concentration (µg/mL) 0.5-2 1-2 3 11-35
Metabolism Unknown Unknown Unknown Unknown
Elimination Urine; 15 days or longer Unknown Unknown unknown
Half-life (h) 91 173 28 24
CSF penetration (%serum) <10 <10 <10 <10
Dosage adjustment in renal impairment None None None None
Dosage adjustment in hepatic None None None None
impairment
CSF, cerebrospinal fluid; IV, intravenous.
Data from Zilberberg MD, Shorr AF, Kollef MH. Secular trends in candidemia-related hospitalization in the United States, 2000-2005. Infect Control Hosp Epidemiol. October 2008;29(10):978-980.

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