T2ii / 21B04: Compare the pharmacology of fluconazole and amphotericin

21B04: Exam Report

Compare the pharmacology of fluconazole and amphotericin

6% of candidates passed this question.

This question exposed an area of the syllabus neglected by the candidates. Answers were generally vague in detail with lots of incorrect facts and generally displayed a very limited knowledge. Antifungal agents are regularly used in critically ill patients either as treatment or prophylaxis. An understanding of the aspects of these drugs with respect to spectrum of activity, mechanism of action, specific PK and PD properties as well as potential side effects would have been the basis for this compare and contrast question. Examiners want to be convinced that the candidates understand the strengths and weaknesses of each drug and in which circumstances one agent might be used in preference to the other.

T2ii / 21B04: Compare the pharmacology of fluconazole and amphotericin

Fluconazole

Amphotericin

Comments

Class

Fluconazole

Azole

Amphotericin

Polyene

Comments

Different class

Use

Fluconazole

Candidiasis/systemic candida infections/antifungal prophylaxis in allogenic hematopoietic cell transplant

Amphotericin

Severe, invasive fungal infections

Cryptococcal meningitis

Comments

Amphotericin used when severe systemic infections due to toxicities associated with IV use

Amphotericin used as induction agent in cryptococcal meningitis, fluconazole used for consolidation and eradication therapy

Presentation

Fluconazole

Tablet 50mg-200mg

IV solution 2mg/ml

Amphotericin

IV solution

Has different formulations – desoxycholate/lipid based formulation

Dose

Fluconazole

Prophylaxis: 100-400mg daily

Treatment: 400-800mg daily

Dose adjustment required with renal impairment

Amphotericin

0.7 – 5mg/kg daily (depending on indication), reduced in severe renal impairment

Route

Fluconazole

IV / PO / PV

Amphotericin

IV /  Nebulized

Comments

Oral route available for fluconazole (due to good OBA)

Mechanism

Fluconazole

Cidal

Amphotericin

Cidal

Comments

Similar cidal properties

MOA

Fluconazole

Inhibit ergosterol synthesis by inhibiting CYP 450 enzyme (inhibit cytochrome lanosterol-α-demethylase which converts lanosterol to ergosterol) → accumulation of lanosterol, perturbation of fungal cell membrane & fungistasis

Amphotericin

Binds ergosterols, disrupting osmotic integrity of cell membrane

(selective action on fungal cells because human cells have cholesterol rather than ergosterol)

Time v Concentration

Fluconazole

Concentration

Amphotericin

Concentration

Spectrum

Fluconazole

Good penetration into all tissues and body fluids

Cryptococcus neoformans

Candida spp  

Amphotericin

Cryptococcus neoformans

Aspergillus Fumigatus

Mucor mucedo

Candida spp

Comments

Fluconazole less effective than amphotericin in candidaemias caused by some non-albican Candida species

PK

A

Fluconazole

100% OBA, rapid absorption

Amphotericin

IV

Comments

Fluconazole can be given orally due to good OBA

D

Fluconazole

Crosses BBB – good CSF penetration, very low protein binding (~10%)

VD equivalent to total body water (~42L)

Amphotericin

High protein binding to plasma proteins >90%

Large VD 280L

Rapid uptake by reticuloendothelial system. Binds to organic anion transporting peptides (important in hepatocyte drug binding), important in key drug interactions (such as tacrolimus)

M

Fluconazole

Metabolised by & cause reversible inhibition of multiple hepatic CYP 450 enzymes (including 3A4, 2C19, 2C9) leading to ↑ concentrations of many drugs/metabolites

Amphotericin

Minimal metabolism

E

Fluconazole

80% of fluconazole renally eliminated unchanged

T½ 30hrs

Amphotericin

Renal elimination of unchanged drug

T½ 24hrs

Comments

Both require dosing adjustment with renal impairment

AE

Fluconazole

GIT: N&V, abdominal pain, diarrhoea, abnormal LFTs, hepatic failure

Allergy: rash, angioedema, SJS

CNS: headache, visual disturbance

CVS: QT prolongation

MET: hypokalaemia

HAEM: thrombocytopenia, agranulocytosis

Amphotericin

GIT: N&V, deranged LFTs

RENAL: nephrotoxicity

Infusion related: Fever, chills, rigors, phlebitis

MET: hypokalaemia, hypomagnesemia

HAEM: anaemia

Comments

Amphotericin has more toxic side effects than fluconazole

Drug interactions

Fluconazole

Caution for use with multiple drugs

QT prolongation effects: amiodarone, erythromycin

CYP interaction: phenytoin, carbamazepine, tacrolimus

Comments

Fluconazole has numerous drug interactions

Resistance

Fluconazole

Increasing resistance in non albicans candidas (esp Candida auris)

Aspergillus

Amphotericin

Chromoblastomycosis, Aspergillus terreus, Candida lusitaniae, Scedosporium spp, and some Fusarium spp

Comments

Amphotericin used in resistant candida infections

Monitoring

Fluconazole

LFT, FBE

Amphotericin

UEC, electrolytes

Comments

Both require monitoring due to risk of hepato/nephrotoxicity

Author: Novia Tan