A Textbook of Clinical Pharmacology and Therapeutics

ANTIFUNGALDRUGTHERAPY 341

POLYENES

AMPHOTERICIN B

Uses

Amphotericinis invaluable in treating life-threatening sys-
temic fungal infections, but has considerable toxicity. Its spec-
trum is broad and includes AspergillusandCandidaspecies,
Blastomyces dermatitidis(which causes North American blasto-
mycosis),Histoplasma capsulatum(which causes histoplasmo-
sis), Cryptococcus neoformans(which causes cryptococcosis),
Coccidioides immitis(which causes coccidioidomycosis) and
Sporotrichum schenckii(which causes sporotrichosis). Resistance
is seldom acquired. Amphotericin is insoluble in water, but can
be complexed to bile salts to give an unstable colloid which can
be administered intravenously. Amphotericin B is normally
given as an intravenous infusion given over four to six hours.
Several liposomal or lipid/colloidal complex amphotericin
preparations have now been formulated, and are less toxic (par-
ticularly less nephrotoxic), but more expensive than the stand-
ard formulation. Liposomal amphotericin is reserved for
patients who experience unacceptable adverse effects from
regular amphotericinor in whom nephrotoxicity needs to be
minimized. Topical amphotericinlozenges or suspension are
used for oral or pharyngeal candidiasis.

Mechanism of action

Amphotericinis a polyene macrolide with a hydroxylated
hydrophilic surface on one side of the molecule and an unsatur-
ated conjugated lipophilic surface on the other. The lipophilic
surface has a higher affinity for fungal sterols than for choles-
terol in mammalian cell membranes and increases membrane
permeability by creating a ‘membrane pore’ with a hydrophilic
centre which causes leakage of small molecules, e.g. glucose
and potassium ions.

Adverse effects

These include:

• fever, chills, headache, nausea, vomiting, and hypotension
  during intravenous infusion.


• reversible nephrotoxicity; this is dose dependent and
  almost invariable. It results from vasoconstriction and
  tubular damage leading to acute renal impairment
  and sometimes renal tubular acidosis.


• tubular cationic losses, causing hypokalaemia and
  hypomagnesaemia;


• normochromic normocytic anaemia due to temporary
  marrow suppression is common.

Pharmacokinetics

Poor gastro-intestinal absorption necessitates intravenous
administration for systemic infections. Amphotericindistrib-
utes very unevenly throughout the body. Cerebrospinal fluid
(CSF) concentrations are 1/40 of the plasma concentration, but
it is concentrated in the reticulo-endothelial system. The t1/2is
18–24 hours. Amphotericinelimination is unaffected by renal
dysfunction.

N YSTAT I N

Nystatinworks in the same way as amphotericin B, but its

greater toxicity precludes systemic use. Its indications are

limited to cutaneous/mucocutaneous and intestinal infections,

especially those caused by Candidaspecies. Little or no nystatin

is absorbed systemically from the oropharynx or gastrointest-

inal tract, and resistance does not develop during therapy.

Preparations of nystatininclude tablets, pastilles, lozenges

or suspension. Patients often prefer topical amphotericin B

becausenystatinhas a bitter taste. Cutaneous infections are

treated with ointment and vaginitis is treated by suppositories.

Adverse effects

Nystatincan cause nausea and diarrhoea when large doses

are administered orally.

Key points

Polyene antifungal drugs

• Wide spectrum of antifungal activity, fungicidal; makes
  ‘pores’ in fungal membranes.


• Available for topical (nystatin and amphotericin)
  treatment of common mucocutaneous fungal infections.


• Amphotericin is used intravenously for deep-seated and
  severe fungal infections (e.g. Aspergillus or
  histoplasmosis).


• Intravenous amphotericin is toxic, causing fever, chills,
  hypotension during infusion, nephrotoxicity, electrolyte
  abnormalities and transient bone marrow suppression.


• Systemic toxicity (especially nephrotoxicity) of
  amphotericin is reduced by using the liposomal/
  lipid/micellar formulations.


• Amphotericin combined with 5-flucytosine may be used
  in severe infections and immunosuppressed patients.

AZOLES

IMIDAZOLES

Imidazoles are fungistatic at low concentrations and fungi-

cidal at higher concentrations. They are used topically and are

active both against dermatophytes and yeasts (e.g. Candida).

Some imidazoles are also used systemically, although they

have limited efficacy and significant toxicity.

Mechanism of action of azoles (imidazoles and

triazoles)

Imidazoles competitively inhibit lanosterol 14-α-demethylase

(a fungal cytochrome-haem P450 enzyme), which is a major

enzyme in the pathway that synthesizes ergosterol from squa-

lene. This disrupts the acyl chains of fungal membrane phos-

pholipids, increasing membrane fluidity and causing

membrane leakage and dysfunction of membrane-bound

enzymes. The imidazoles have considerable specificity/affinity

for fungal cytochrome-haem P450 enzymes. Azole resistance

occurs due to mutations in the gene encoding for lanosterol

14-α-demethylase (ERG11) or less commonly due to increased

azole efflux by fungal drug transport proteins.