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