A Textbook of Clinical Pharmacology and Therapeutics

ANTIFUNGALDRUGTHERAPY 343

therapy is adequate though more frequent dosing is required
for voriconazole. Adverse effects include gastro-intestinal
upsets, rashes and hepatitis with rare case of hepatic failure.
Voriconazolecauses visual disturbances. CYP450 (especially
CYP3A but CYP2C9CYP3A in the case of voriconazole)
inhibition related drug–drug interactions are problematic for
both agents. Drugs which decrease gastric acid (e.g. proton-
pump inhibitors) reduce the bioavailablity of both agents
and drugs that induce hepatic CYP3A decrease systemic drug
concentrations. Neither drug should be used in pregnancy and
i.v. formulations of both should be avoided in patients with
significant renal dysfunction (GFR 30 mL/min) because
of accumulation of the drug diluent (sulphobutylether beta
cyclodextrin sodium) which has nephro- and hepatoxic effects
in animals.
Posaconazoleis a novel agent with considerable potential
due to its extended antifungal spectrum.

Key points

Azole antifungal drugs

• Relatively wide spectrum of antifungal activity,
  fungistatic, but fungicidal with higher concentrations.


• Impair ergosterol biosynthesis by inhibiting
  lanosterol 14-alpha-demethylase (fungal cytochrome
  enzyme).


• Available as intravenous, oral and topical formulations.


• Can be used as therapy for superficial (e.g. Candida)
  and serious deep-seated (e.g. Cryptococcus) fungal
  infections.


• Fluconazole, itraconazole and voriconazole are
  currently much more widely used than ketoconazole.


• Azole-related common toxicities are gastro-intestinal
  upsets, rashes, hepatitis and CYP3A inhibition-related
  drug–drug interactions.

ALLYLAMINES

TERBINAFINE

Terbinafineis an allylamine and is fungicidal. It may be

administered orally to treat ringworm (Tinea pedis,T. crurisorT.

corporis) or dermatophyte infections of the nails. It is given once

daily for two to six weeks (longer in infections of the nailbed, as

an alternative to griseofulvin, see below). It acts by inhibiting

the enzyme squalene epoxidase, which is involved in fungal

ergosterol biosynthesis. It interferes with human CYP450, but

only to a limited extent (e.g. 10–15% increase in ciclosporin

concentrations). It is well absorbed, strongly bound to plasma

proteins and concentrated in the stratum corneum. It is elimi-

nated by hepatic metabolism with a mean elimination t1/2of 17

hours. Its major side effects are nausea, abdominal discomfort,

anorexia, diarrhoea and rashes (including urticaria). Dose

reduction is needed in hepatic failure or if co-prescribed with

drugs which are potent CYP3A inhibitors (e.g. HIV protease

inhibitors). Rifampicin increases terbinafine metabolism,

requiring a dose increase. Naftifine, another allylamine, is

available for topical administration.

ECHINOCANDINS

Caspofunginandmicafunginare novel echinocandins that

are fungicidal to susceptible species. Echinocandins are semi-

synthetic lipopeptides.

Use

Echinocandins are active against Candida and Aspergillus

species. They are used primarily for fungal infections that are

resistant to azoles or where patients are intolerant of azoles

and are administered by intravenous infusion, usually once

daily.

Mechanism of action

Echinocandins are non-competitive inhibitors of 1,3-β-Dglucan

synthase, an enzyme necessary for synthesis of a glucose poly-

mer crucial to the structure and integrity of the cell walls of

some fungi. Fungal cells unable to synthesize this polysaccha-

ride cannot maintain their shape and lack adequate rigidity to

resist osmotic pressure, which results in fungal cell lysis.

Glucan also appears essential for fungal cell growth and divi-

sion. The mechanism of action of echinocandins is unique and

drugs of this class are potentially additive or synergistic with

polyenes and azoles.

Adverse effects

Adverse effects (usually mild and seldom problematic) include:

• infusion phlebitis and fever, histamine-like infusion
  reactions, if infused rapidly;


• infrequently nausea, diarrhoea, hyperbilirubinaemia;


• rarely hepatitis, leukopenia.

Pharmacokinetics

Caspofungin andmicafunginare not absorbed from the

gastro-intestinal tract and are administered intravenously.

Both agents are eliminated by hydrolysis and N-acetylation

to inactive metabolites. The mean elimination t1/2forcaspo-

funginis 9–11 hours and for micafunginis 11–17 hours.

Urine excretion of parent drug is insignificant and dose

reduction is not indicated in renal failure. The dose of caspo-

funginshould, however, be reduced in significant hepatic

dysfunction.

Drug interactions

These are minimal compared to the azoles. Ciclosporin

increases caspofunginAUC by 35% and micafunginincreases

the bioavailability of sirolimusandnifedipine.

Other agents in this expanding class include anidulafungin.