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65 Cards in this Set
- Front
- Back
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MOA of Amphotericin B - Polyene
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- Inhibits ergosterol synthesis
- Forms pores in the membranes of the fungal cell - --> K+ leakage - Induction of oxidative stress |
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Species AmpB is cidal against
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Cidal - Aspergillus + candida
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Side effects of AmpB
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Hepatotoxicity
Nephrotoxicity |
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Spectrum of AmpB
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Most yeasts and moulds
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Aspergillus species Amp is INNACTIVE against
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A. terreus
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Clinical uses of AmpB
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Cryptococcal
zygomycosis Empirical therapy for immunosupressed |
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Biochemistry of AmpB molecules
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- Produced from streptomyces
- Cyclic amphiphatic molecules - Hydrophobic site binds to sterols |
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MOA of Flucytosine (pyrimidine) to cause DNA inhibition
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Enters cell via cytosine permease
converted to 5-FU UPRT converts 5-FU to FdUMP FdUMP inhibits thymidlate synthetase DNA INHIBITION |
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MOA of flucytosine --> Translation disruption
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Enters cell via cytosine permease
converted to 5-FU 5-FU--> flurodine triphosphate incorporated into RNA Disrupts translation |
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Spectrum of flucytosine
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Cryptotoccus
Candida |
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Flucytosine NOT ACTIVE
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Aspergillus
most moulds |
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Clinical use of flucytosine
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IV
AmpB combination Rarely used Good for cryptococcal meningitis |
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Example of subcutaneous fungal infection
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chromoblastomycosis
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MOA allylamines
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Squaline epoxidase inhibition (ERG-1 Gene product)
Cidal - Squaline accumulation Static - ergosterol deficiency |
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Spectrum for terbinafine
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Dermatophytes
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Clinical use of terbinafine
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Oral candidiasis
onichomycosis difficult aspergillosis cases in combination (ampB) |
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ADME of voriconazole
1/2 - 6 hours |
A - 96% oral - variable with food
D- 58% protein bound M- Extensive hepatic (34A, 2C9, C19) E- 80% renal, 20% faecal |
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posconazole ADME
1/2 25 hours |
A - 8-48% vairbale, increase dosing increase absorption
D - Highly protein bound M - Minimal oxidation and glucocordination E - 70 % renal 13% faecal |
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Flucytosine resistance mechanisms - point mutations
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Cytosine permease prevents entry
Deaminase prevents FC to FU UPRT - most common |
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Aspergillus resistance to flucytosine
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In vitro animal saw sensitivity at pH5
Maybe as cytosine permease is a H+ symport No clinical data |
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Two yeasts developing rapid flucytosine resistance
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candida
cryptococcus |
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Cros resistance to flucytosine
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7/11 C. lusitaniae azole resistant
Stop codon --> truncated protein conferred azole and flucytosine resistance |
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Mechanisim of amphotericin resistance
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ERG 3 mutation --> sterol demethylase
Increased catalase --> reduced oxidative damage Reduced ergosterol --> less target (C.Lusitaniae) |
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Candida efflux and Azole resistance..
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CDR genes (ABC family) 1/2/
Regulated by CR (DRE--> increase CDR1+2) TAC-1 --> GOF mutation and constitutive CDR expression EFFLUX TRANSPORTERS |
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Target alteration --> azole resistance
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14 a lanosterol demethylase mutation conferes resistance in some cases for Candida
Encoded by CYP15A |
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Enzyme upregulation conferring azole regulation
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CDR1 and 2 upregulation
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Bypass pathways for azole resistance
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ERG3 mutation results in the accumulation of a less toxic metabolite which the cell can tolerate.
14a methyl-fecosterol |
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MDR in candida
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Proton antiport
increased MDR expression results in increased resistance |
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When is therapeutic drug monitoring indicated?
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Variation in absorption
Drug interactions Toxicity at high concentration Levels correlate with efficacy |
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explain LC-MS/MS
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Extract serum
HPLC purification Ionisation and break purified drug Mass spec Measure levels |
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Bioassays for TDM...
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Old rarely used
poor reproducibility only gives the accumulative total not specific |
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Why are azoles indicated for TDM
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FCZ - Renal variability
ICZ - Formulation and toxicity issues PCZ - Absorption variation VCZ - CYP450 genetic polymorphisms |
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predictor of clinical outcome other than MIC
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Azoles - AUC/MIC (measures total drug given) >25
Polyenes - Cmax/MIC - Maximum [drug]/MIC |
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Factors affecting outcome of therapy
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Host - immunostatus
Fungi - virulence, disseminating ability Pharmacokinetics - Dosing, Delivery, interaction |
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CLSI M27A3 yeast method .....
(6 isolates vs 1 agent) |
1. RPMI + 2% glucose media pH7
2. Saline innoculum solution (OD measured) 3. Innoculate plates - Read by eye |
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echinocandin resistance
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FSK1 (Bglucan 1-3- synthetase) mutation
candida are diploid . heterozygus mutation --> less resistance |
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Paradoxical resistance with echinocandins
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Aspergillus exhibits a quadrophasic response
Possibly due to increased cell wall biosynthesis component os induction of cell wall integrity pathway |
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PD of flucytosine
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time dependant
limited PAFE T > MIC 20-40% = best outcome |
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PD of polyenes
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[dependant]
long PAFE less frequent high doses |
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PD of echinocandins
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[dependant]
long PAFE 4 X MIC Cmax = best |
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PD aozles
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time dependant
long PAFE AUC/MIC > 25 = best |
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CYP450 34a metabolism of azoles occurs when?
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before absorption
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Azole with the fewest interaction
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fluconazole
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Metabolism and inhibitors of CYP byt azole
34A 2C9 2C19 |
34A - met: ICZ Inhi: PCZ
2C9 - Met: VCZ inhi: FCZ 219C - met: VCZ inh: VCZ |
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interactions of azoles and CYP with other drugs 3 outcomes
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azole inhibits CYP --> increased other drug
Drug inhibits CYP --> increased Azole Drug increases CYP --> decreased drug and azole |
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PK of fluconazole (ADME)
1/2 31 hours |
A - 95% oral bioavailability
D- High tissue concentration M - 34A minimal hepatic E - 80% mainly unchanged in urine |
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ADME itraconazole
1/2 24 hours |
A - 50%
D - protein bound M - 34A extensive hepatic --> hydroxyitraconazole E - 35% renal + 54% faecal |
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ADME Amphotericin B
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A - IV only
D - 95% protein bound M - no metabolites identified E - 21% urine 43% hepatobillary |
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ADME fllucytosine
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A - 75-90%
D - Minimal protein binding M - minimal hepatic, limited deamination E - >90% unchanged in urine |
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7 considerations for therapy
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1. severity of infection
2. underlying disease 3. concominant drugs 4. site of infection 5. spectrum 6. indications 7. cost |
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Factors affecting in vitro MIC
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pH - low pH increased MIC
media interactions incubation temp innoculum size incubation duration |
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MEC ?
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minimum effective concentration
- caues hyphal distortion in aspergillus with caspofungin |
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problems wiht E-test
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Azole trailing end
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explain disk diffusion
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yeast N base plus aspargine
C- kefyr as a control (-) poor reproducibility |
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yeast one sensititre explain
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6-8 agents agains 1 isolate
colour change indicator |
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Pharmacogenomics absorption
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GI pH (ICZ and PCZ)
drug transportes (PCZ) - P glycoprotein accounts for upto 70% variability |
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PG Distribution
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protein binding varies between individuals by around 10%
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PG of metabolism
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CYP sn polymorphisms
C219 major voriconazole metabolism SNPs account for up to 50% variability Poor metabolises have higher plasma concentration |
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Echinocandins MOA
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bind FSK1 gene product - b1-3 glucan sunthetase
inhibit both FSK isoforms low toxicity |
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Echinocandins spectrum
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static - aspergillus
Cidal - candida PCP |
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echinocandins innactive against
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cryptococcus
fusarium zygomycetes |
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overview of echinocandins
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modified secondary metabolite with reduced toxicity
new class available for invasive mycoses |
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MOA triazoles
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inhibit lanosterol 14 a demethylase
result in toxic metabolite build up generally static but cidal at high concentration |
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Azole with CNS distribution
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Fluconazole
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spectrum of azoles
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FCZ - most yeasts
ICZ - Krusei _ most moulds PCZ - yeasts + moulds + zygomycetes |
