An Introduction to Anti-fungal Pharmacology The following slides were generously supplied by Professor Russell E. Lewis, Pharm.D., BCPS University of Houston College of Pharmacy, University of Texas M.D. Anderson Cancer Center. With lecture notes written by Hannah Woodcock and Jenny Bartholomew, University of Manchester, UK.
51
Embed
An Introduction to Anti-fungal Pharmacology The following slides were generously supplied by Professor Russell E. Lewis, Pharm.D., BCPS University of Houston.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
An Introduction to Anti-fungal Pharmacology
The following slides were generously supplied by
Professor Russell E. Lewis, Pharm.D., BCPS
University of Houston College of Pharmacy, University of Texas M.D. Anderson Cancer Center.
With lecture notes written by Hannah Woodcock and Jenny Bartholomew, University of Manchester, UK.
Types of fungal infections - Mycoses
Superficial mycoses Affect the skin, hair and nails
Subcutaneous mycoses (tropical) Affect the muscle and connective tissue
immediately below the skin Systemic (invasive) mycoses
Involve the internal organs Primary vs. opportunistic
Allergic mycoses Affect lungs or sinuses Patients may have chronic asthma, cystic fibrosis
or sinusitisThere is some overlap between these
groups
What are the targets for antifungal therapy?
Cell membraneFungi use principally ergosterol instead of cholesterol
Cell WallUnlike mammalian cells, fungi have a cell wall
DNA SynthesisSome compounds may be selectively activated by fungi, arresting DNA synthesis.
Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001
astemizole, corticosteroid, and theophylline levels Many of these drug interactions are
severe Drugs that increase gastric pH will decrease
blood levels of ketoconazole Antacids, omeprazole, H2 blockers
Ketoconazole - Dose
Serious infections 800 mg/day PO Other: 200-400 mg/day PO
Cost $2.50 per 200 mg tablet
Fluconazole
Well tolerated IV/PO
formulations Favorable
pharmacokinetics
Fungistatic Resistance is
increasing Narrow
spectrum (Drug
interactions)
Advantages Disadvantages
Fluconazole - spectrum
Good activity against C. albicans and Cryptococcus neoformans
Non-albicans Candida species more likely to exhibit primary resistance
C. krusei > C. glabrata > C. parapsilosis
C. tropicalis
C. kefyr
Always resistant Sometimes resistant
Fluconazole - resistance Primary resistance (seen in severely ill or
immunocompromised patients) Selection of resistant species or
subpopulations Replacement with more resistant strain
Secondary resistance (seen in patients with AIDS who experienced recurrent orophayrngeal candidiasis and received long-term fluconazole therapy) Genetic mutation Upregulation of efflux pumps
Mechanisms of antifungal resistance
Target enzyme modification
Ergosterol biosynthetic pathway
Efflux pumps Drug import
White TC, Marr KA, Bowden RA. Clin Microbiol Review 1998;11:382-402
Fluconazole - What is not covered
Candida krusei +/- Candida glabrata Aspergillus species and other
moulds
Fluconazole - Pharmacokinetics
Available as both IV and PO Bioavailibility > 90%
Linear pharmacokinetics t 1/2 = ~24 hours Cmax (400 mg IV) = 20 µg/ml (steady state) Protein binding < 12% Vd 0.85 L/kg (widely distributed) >90% excreted unchanged through the
kidney
Fluconazole - adverse effects/monitoring
N&V, rash: More likely with high doses and in AIDS
patients Asymptomatic increase in LFTs (7%)
Drug interactions: May increase phenytoin, cyclosporin,
rifabutin, warfarin, and zidovudine concentrations
Rifampin reduced fluconazole levels to half (even though FLU is not a major substrate)
The drug of choice for: Cryptococcal meningitis Mucormycosis (zygomycosis) Invasive fungal infection, not
responding to other therapy
Amphotericin B - Dosing and Administration
“Test dose” 1.0 mg in 25-100ml 5% dextrose infused over 10 minutes used to evaluate possibility of anaphylactic reaction No longer recommended, current product has
fewer impurities Current recommendation- Start with ~30% of
target dose, infuse for 15 minutes, stop infusion, and monitor patient for adverse effects before resuming infusion
Rapidly escalate to full dosages within 48-72 hours
Delay in giving full dose = worse clinical outcome