BIOL2212 antifungi pyrimidines and polyenes

what is the only pyrimidine antifungal in clinical use

5-fluorocytocine (flucytosine)

how is 5-fluorocytosine taken up

by fungal specific cytosine permease

is 5-fluorocytosine the active form of the drug

conv into 5-fluorouracil by deaminase

found only in fungi and bact)

mech of action of 5-fluorouracil (5-fluorocytosine)

fluorouridine monophosphate, conv to triphosphate and incorp into RNA (disrupt transl)

also conv to FdUMP, which inhis thymidylate synthetase (inhib DNA synth)

as cant do dUMP to dTMP reaction

how is 5-fluorocytosine administered

oral

water sol so readily absorbed, gives wide distribution in tissues and body fluids (CSF too)

clinical of use of 5-FC

res develops quickly in candida and cryptococcus when monotherapy

use with amphotericin B or fluconazole

use for systemic infections

is 5-FC metabolised by humans

not or minimally by microflora (as dont have deaminase so not conv to 5-FU)

half life 3-6 hrs so req dose 3-4x per day

excrete in urine

toxicity of 5-FC

v low (some conv to 5-FU by flora)

myelosuppression if use too long

liver toxicity

define leucopenia

low number of WBC

define thrombocytopenia

low number of platelets

define aplastic anaemia

low number of red blood cells

%-FC drug intertions

brivudine (antiviral) inhibs DPD which degrades 5FU so pot 5FU toxicity

mechanism of resistance to 5FC

aff cytosine permease (less uptake of 5FC) in cell memb

aff cytosine deaminase (less conv to 5FU)

aff uracil phospho-ribosyl transferase (cant prod FUMP (cant incorp into RNA))

polyene antifungals

natural products of Streptomyces sp.

Nystatin and amphotericin B

mode of action of polyenes

damage cells by increase permeability

bind sterols, partiularly ergosterol in p memb via their macrolide rings (Hphobic part)

distort memb, so leak

how does amphoteracin B also damage fungi that nystatin doesnt

oxidative damage thru auto-oxidation (mech unclear)

Amp B res mutants als res to H2O2 damage

diff models that AmpB disrupts cell memb

pore formation

ergosterol binding

sponge model

and cause oxidative damage in cell

structure of amp B, ergosterol and cholesterol

long aliphatic mols

ergosterol and cholesterol have long chain with h phobic head.

amp b is similar but large hphobic region, used to bind ergosterol

spectrum of activity of AmpB and nystatin

ampB- broad spectrum, yeast and molds (not aspergillus)

Nystatin- most yeasts are sensitive

is amphotericin B deoxycholate used nowadays

no, just use amp B instead

as had signif infusion related and kidney toxicity

Now use liposomal formulations of it (ambisome)

administer amp b vs nystatin

amp B, IV

nystatin only topical, not abs orally and too toxic for IV

is amp B used in empirical treatment of immunocomp suspected of fungal infections

yes

and for candidosis, aspergillosis, cryptococcosis and occasionally topically

what is nystatin used for

treat oral of vaginal candidosis

is ambisome/amp B effective as a prophylatic

NO

when is amphoteracin use best

not prophylatically

but for patients with fever (febrile episode), neutropenic and antibiotics arent working (so suspect fungal infection)

what is conventional amphotericin

the deoxycholate version

(new formulations/non conv are lipid formulations)

how is ambisome administered

IV

once daily

most binds proteins in body

excreted mostly unchanged, no need for monitoring

side effects of amp B

less with liposomal formulations

get infusion related toxicity and nephrotoxicity

hypokalemia (low K levels)

(so dont give with nephrotoxic drugs or diuretics)

dont use with 5FC as nephrotoxicity may reduce 5FC clearance so get myelosupp

why is amb b resistance not prominant

targets a non-protein (so cant just mut)

muts often assoc with severe fitness loss

mechanism of resistance to amphotericin b in candida

mut in ERG genes (code for enzymes inv in ergosterol synth)

rsult in increased MIC

reduced or altered ergosterol/content content in memb

increased catalase activity may reduce oxidative damage caused by amp B

main use of 5-FC

cryptococcal meningitis