DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Membrane function
amphotericin B
Cell wall synthesis
caspofungin
Ergosterol synthesis
fluconazole
itraconazole
voriconazole
naftifine
terbinafine
Nucleic acid
synthesis
5-fluorocytosine
Figure 57–1. Sites of action of antifungal drugs. Amphotericin B
and other polyenes, such as nystatin, bind to ergosterol in fungal
cell membranes and increase membrane permeability. The imidazoles
and triazoles, such as itraconazole and fluconazole,
inhibit 14-α-sterol demethylase, prevent ergosterol synthesis,
and lead to the accumulation of 14-α-methylsterols. The allylamines,
such as naftifine and terbinafine, inhibit squalene epoxidase
and prevent ergosterol synthesis. The echinocandins, such
as caspofungin, inhibit the formation of glucans in the fungal
cell wall.
Drug Formulations. There are currently four formulations of amphotericin
B commercially available: conventional amphotericin B
(C-AMB), liposomal amphotericin B (L-AMB), amphotericin B
lipid complex (ABLC), and amphotericin B colloidal dispersion
(ABCD). Table 57–2 summarizes the pharmacokinetic properties of
these preparations.
C-AMB (Conventional amphotericin B, FUNGIZONE). Amphotericin B
is insoluble in water but is formulated for intravenous infusion by
complexing it with the bile salt deoxycholate. The complex is marketed
as a lyophilized powder for injection. C-AMB forms a colloid
in water, with particles largely <0.4 μm in diameter. Filters in intravenous
infusion lines that trap particles >0.22 μm in diameter will
remove significant amounts of drug. Addition of electrolytes to infusion
solutions causes the colloid to aggregate.
ABCD. Amphotericin B colloidal dispersion (AMPHOTEC, AMPHOCIL)
contains roughly equimolar amounts of amphotericin B and cholesteryl
sulfate formulated for injection. Like C-AMB, ABCD forms a
colloidal solution when dispersed in aqueous solution. ABCD provides
much lower blood levels than C-AMB in mice and humans. In
a study in patients with neutropenic fever comparing daily ABCD
(4 mg/kg) with C-AMB (0.8 mg/kg), chills and hypoxia were significantly
more common with ABCD than with C-AMB (White et al.,
1998). Hypoxia was associated with severe febrile reactions. In a
comparison of ABCD (6 mg/kg) and C-AMB (1-1.5 mg/kg) in invasive
aspergillosis patients, ABCD was less nephrotoxic than C-AMB
(49% vs. 15%) but caused more fever (27% vs. 16%) and chills (53%
vs. 30%) (Bowden et al., 2002). Administration of the recommended
ABCD dose over 3-4 hours and use of premedication to reduce
febrile reactions are advised, particularly with initial infusions. ABCD
is approved at a recommended dose of 3-4 mg/kg intravenously daily
for patients with invasive aspergillosis who are not responding to or
are unable to tolerate C-AMB.
L-AMB. Liposomal amphotericin B is a small, unilamellar vesicle
formulation of amphotericin B (AMBISOME). The drug is supplied
as a lyophilized powder, which is reconstituted with sterile water
for injection. Blood levels following intravenous infusion are
almost equivalent to those obtained with C-AMB, and because
L-AMB can be given at higher doses, blood levels have been
achieved that exceed those obtained with C-AMB (Boswell et al.,
1998) (Table 57–2). Amphotericin B accumulation in the liver and
spleen is higher with L-AMB than with C-AMB. Adverse effects
include nephrotoxicity, hypokalemia, and infusion-related reactions,
such as fever, chills, hypoxia, hypotension, and hypertension,
but these do not commonly lead to drug discontinuation.
Infusion-related pain in the back, abdomen, or chest occurs in
occasional patients, usually with the first few doses. Anaphylaxis
also has been reported. As empirical therapy or prophylaxis in
febrile neutropenic patients, CAMB and L-AMB are equivalent.
As induction therapy of disseminated histoplasmosis in AIDS
patients, L-AMB 3 mg/kg was superior to C-AMB 0.7 mg/kg
(Johnson, 2002). L-AMB is approved for initial therapy of cryptococcal
meningitis of AIDS patients and is listed as an alternative
to C-AMB for induction therapy of both disseminated histoplasmosis
and cryptococcal meningoencephalitis in AIDS patients
(Kaplan et al., 2009). L-AMB is approved for empirical therapy of
fever in the neutropenic host not responding to appropriate antibacterial
agents, as well as for salvage therapy of aspergillosis and
candidiasis. The recommended daily intravenous dose for empirical
therapy is 3 mg/kg; for treatment of mycoses, the dosage is
3-5 mg/kg. L-AMB also is effective in visceral leishmaniasis at
doses of 3-4 mg/kg daily. The drug is administered in 5% dextrose
in water, with initial doses infused over 2 hours. If well tolerated,
infusion duration can be shortened to 1 hour. Doses up to
10 mg/kg have been used but are associated with higher toxicity
and, in one randomized trial of aspergillosis, no improvement
in efficacy (Cornely, 2007a).
ABLC (ABELCET). Amphotericin B lipid complex is a complex
of amphotericin B with lipids (dimyristoylphosphatidylcholine
and dimyristoylphosphatidylglycerol). ABLC is given in a dose of
5 mg/kg in 5% dextrose in water, infused intravenously once daily
over 2 hours. Blood levels of amphotericin B are much lower with
ABLC than with the same dose of C-AMB. ABLC is effective in a
variety of mycoses, with the possible exception of cryptococcal meningitis.
The drug is approved for salvage therapy of deep mycoses.
The three lipid formulations collectively appear to reduce
the risk of the patient’s serum creatinine doubling during therapy
by 58% (Barrett et al., 2003). In patients at high risk for nephrotoxicity,
ABLC is more nephrotoxic than L-AMB (Wingard et al.,
2000). In some patients, the additive burden of amphotericin B
nephrotoxicity can help precipitate advanced renal failure, with
attendant morbidity. Infusion-related reactions are not consistently
reduced with the use of lipid preparations. ABCD causes more
infusion-related reactions than C-AMB. Although L-AMB reportedly
causes fewer infusion-related reactions than ABLC during
the first dose (Wingard et al., 2000), the difference depends on
whether premedication is given and varies considerably between
patients. Infusion-related reactions typically decrease with subsequent
infusions.