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

1576 with cryptococcosis, but the combination has substantial GI toxicity
with no evidence that flucytosine adds benefit (Larsen et al., 1994).
In cryptococcal meningitis of non-AIDS patients, the role of flucytosine
is more conjectural. The addition of flucytosine to ≥6 weeks of
therapy with C-AMB runs the risk of substantial bone marrow suppression
or colitis if the flucytosine dose is not promptly adjusted
downward as amphotericin B–induced azotemia occurs. In the 2008
IDSA guidelines for the treatment of cryptococcal meningoencephalitis,
addition of flucytosine (100 mg/kg orally in four divided doses)
is recommended for the first 2 weeks of treatment with amphotericin
B in AIDS patients. A similar practice is often used in HIV-negative
patients but the benefit is unknown (Pappas et al., 2001).
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Untoward Effects. Flucytosine may depress the bone marrow and
lead to leukopenia and thrombocytopenia; patients are more prone to
this complication if they have an underlying hematological disorder,
are being treated with radiation or drugs that injure the bone marrow,
or have a history of treatment with such agents. Other untoward
effects—including rash, nausea, vomiting, diarrhea, and severe enterocolitis—have
been noted. In ~5% of patients, plasma levels of
hepatic enzymes are elevated, but this effect reverses when therapy
is stopped. Toxicity is more frequent in patients with AIDS or
azotemia (including those who are receiving amphotericin B concurrently)
and when plasma drug concentrations exceed 100 μg/mL.
Toxicity may result from conversion of flucytosine to 5-fluorouracil
by the microbial flora in the intestinal tract of the host.
Imidazoles and Triazoles
The azole antifungals include two broad classes, imidazoles
and triazoles, which share the same antifungal
spectrum and mechanism of action. The systemic triazoles
are metabolized more slowly and have less effect
on human sterol synthesis than the imidazoles. Because of
these advantages, new congeners under development are
mostly triazoles. Of the drugs now on the market in the
U.S., clotrimazole, miconazole, ketoconazole, econazole,
butoconazole, oxiconazole, sertaconazole, and sulconazole
are imidazoles; terconazole, itraconazole, fluconazole,
voriconazole, posaconazole, and isavuconazole (an
experimental drug) are triazoles. The topical use of azole
antifungals is described in the second section of this
chapter. The basic triazole structure is:
Mechanism of Action. At concentrations achieved following systemic
administration, the major effect of imidazoles and triazoles on fungi is
inhibition of 14-α-sterol demethylase, a microsomal CYP (Figure 57–1).
Imidazoles and triazoles thus impair the biosynthesis of ergosterol
for the cytoplasmic membrane and lead to the accumulation
of 14-α-methylsterols. These methylsterols may disrupt the close
packing of acyl chains of phospholipids, impairing the functions of
certain membrane-bound enzyme systems, thus inhibiting growth of
the fungi. Some azoles directly increase permeability of the fungal
cytoplasmic membrane, but the concentrations required are likely
only obtained with topical use.
Antifungal Activity. Azoles as a group have clinically useful activity
against Candida albicans, Candida tropicalis, Candida parapsilosis,
Candida glabrata, Cryptococcus neoformans, Blastomyces dermatitidis,
Histoplasma capsulatum, Coccidioides spp., Paracoccidioides
brasiliensis, and ringworm fungi (dermatophytes). Aspergillus spp.,
Scedosporium apiospermum (Pseudallescheria boydii), Fusarium, and
Sporothrix schenckii are intermediate in susceptibility. Candida krusei
and the agents of mucormycosis are more resistant. Thus, these drugs
do not have any useful antibacterial or antiparasitic activity, with the
possible exception of antiprotozoal effects against Leishmania major.
Posaconazole has slightly improved activity in vitro against the agents
of mucormycosis.
Resistance. Azole resistance emerges gradually during prolonged azole
therapy, causing clinical failure in patients with far-advanced HIV
infection and oropharyngeal or esophageal candidiasis. The primary
mechanism of resistance in C. albicans is accumulation of mutations
in ERG11, the gene coding for the 14-α-sterol demethylase. These
mutations protect heme in the enzyme pocket from binding to the azole
but allow access of the natural substrate for the enzyme lanosterol.
Cross-resistance is conferred to all azoles. Increased azole efflux by
both ATP-binding cassette (ABC) and major facilitator superfamily
transporters can add to fluconazole resistance in C. albicans and C.
glabrata. Increased production of C14-α-sterol demethylase is another
potential cause of resistance. Mutation of the C5,6 sterol reductase gene
ERG3 also can increase azole resistance in some species.
Primary azole resistance has been described in some isolates of
Aspergillus fumigatus with increased azole transport and decreased
ergosterol content, but the clinical significance is unknown. Decreased
fluconazole susceptibility has been described in Cryptococcus neoformans
isolated from AIDS patients failing prolonged therapy.
Interaction of Azole Anti-Fungals with Other Drugs. The azoles
interact with hepatic CYPs as substrates and inhibitors (Table 57–3),
providing myriad possibilities for the interaction of azoles with
many other medications. Thus, azoles can elevate plasma levels of some
co-administered drugs (Table 57–4). Other co-administered drugs can
decrease plasma concentrations of azole antifungal agents (Table 57–5).
As a consequence of myriad interactions, combinations of certain drugs
with azole antifungal medications may be contraindicated (Table 57–6).
Ketoconazole
Ketoconazole, administered orally, has been replaced by itraconazole
for the treatment of all mycoses except when the lower cost of ketoconazole
outweighs the advantage of itraconazole. Itraconazole lacks
ketoconazole’s corticosteroid suppression while retaining most of ketoconazole’s
pharmacological properties and expanding the antifungal
spectrum. Ketoconazole sometimes is used to inhibit excessive production
of glucocorticoids in patients with Cushing’s syndrome
(Chapter 42) and is available for topical use, as described later.
Itraconazole
This synthetic triazole is an equimolar racemic mixture
of four diastereoisomers (two enantiomeric pairs), each