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THERAPY USING ANTIFUNGALS AND ANTIVIRALS
Douglas Black, Pharm.D.Associate ProfessorSchool of Pharmacy
University of [email protected]
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CLASSIFICATION OF FUNGI
YeastsDimorphic
fungiMolds
Candida Blastomyces Aspergillus
Cryptococcus
Coccidioides Fusarium
Trichosporon
Histoplasma Rhizopus
Sporothrix Mucor
Absidia
Pseudallescheria
(Scedosporium)
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MOST COMMONLY ISOLATED SPECIES OF CANDIDA
C. albicansC. tropicalisC. parapsilosis C. kefyrC. glabrata C. kruseiC. guillermondiiC. lusitaniae
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LONGİTUDİNAL STUDİES: A TEN-YEAR FUNGEMİA SURVEY
0
20
40
60
80
100
120
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998
albicans %
non-albicans %
Krcmery V Jr. et al. DMID 2000; 36: 7. Slovak Republic
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HISTORY OF ANTIFUNGAL DRUGS
1950sNystatin
Amphotericin BGriseofulvin
1960sMiconazole Clotrimazole
1970sFlucytosine
1980sKetoconazole
1990sFluconazole
Itraconazole capsItraconazole soln
TerbinafineLipid Ampho
2000sCaspofunginVoriconazole
MicafunginAnidulafunginPosaconazole
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AMPHOTERICIN B DEOXYCHOLATE
Good FungicidalBroad spectrumRelatively
inexpensive
Not so goodA few holes in
coverageComplex
pharmacokineticsSignificant IRAEsNephrotoxicity
-glomerular-tubular
Hematologic toxicityDifficult dosing
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SUMMARIZING THE AMPHO B LIPID FORMULATIONS
• Possibly more effective than amphotericin B in certain circumstances (liposomal better than ABLC?)
• Less toxic (IRAEs, kidney)
• Liposomal amphotericin B is less toxic than ABLC
• Expensive
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THE HIGH COST OF LIPID AMPHO FORMULATIONS
Cost in a 70 kg patient
DAILY DOSEAMB (1 mg/kg)ABLC (5 mg/kg)L-AMB (5 mg/kg)
0
100
200
300
400
500
600
AMBABLCL-AMB
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FLUCYTOSINE (5-FC)
55’’-fluorodeoxyuridine -fluorodeoxyuridine mmonophosphateonophosphate (F-dUMP) (F-dUMP)
thymidylate synthase inhibitorthymidylate synthase inhibitorinhibits DNA synthesisinhibits DNA synthesis
55’’-fluoro-UTP-fluoro-UTP (FUTP) (FUTP)incorporated into RNAincorporated into RNA
disrupts protein synthesisdisrupts protein synthesis
5-FC Intracellular 5-FC
5-FU
5’-fluorouridine monophosphate
(FUMP)
phos x2
CP CD
UPRTase
UMP PPase
ENZYMES:CP = cytosine permeaseCD = cytosine deaminaseUPRTase = uracil phosphoribosyl transferaseUMP Ppase = UMP pyrophosphorylase
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A SUMMARY OF FLUCYTOSINE
Good Activated by fungal
enzymesUnique mechanism
of actionExcellent tissue
penetrationSimple renal
eliminationSerum
concentrations can be monitored
Not so goodSomewhat narrow
spectrumFrequent dosing,
large capsulesBone marrow
suppressionHepatotoxicitySecondary resistanceExpensive (about
$6.30 per 500mg capsule)
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AZOLE ANTIFUNGALS AVAILABLE IN THE US
Four systemic drugsKetoconazole (Nizoral)Fluconazole (Diflucan)Itraconazole (Sporanox)Voriconazole (Vfend)
Topical butoconazole, clotrimazole, miconazole, terconazole, and tioconazole are all available for vulvovaginal candidiasis
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TOXICITIES AND DRUG INTERACTION POTENTIAL (EXCEPT
VORI)
Toxicityketoconazole > itraconazole > fluconazole
DI potential ketoconazole > itraconazole >
fluconazole
Pregnancyall topical azoles are considered safe (avoid systemic administration)
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ANTICANDIDAL ACTIVITY OF VORICONAZOLE
C. albicans 0.015-0.5C. parapsilosis 0.015-
0.125C. kefyr 0.015C. tropicalis 0.03-1C. glabrata 0.25-4C. krusei 0.25-2C. lusitaniae 0.5
MIC90
Vori MICs tend to be higher for isolates with high fluconazole MICs
The higher MICs of C. glabrata and C. krusei are of uncertain clinical relevance
Matar et al. AAC 2003; 47: 1647; Chryssanthou et al. JCM 2002; 40: 3841; Laverdiere et al. JAC 2002; 50: 119; Pelletier et al. J Med Microbiol 2002; 51: 479; Pfaller et al. DMID 1999; 35: 19; Uzun et al. DMID 2000; 38: 101
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OTHER TIDBITS ABOUT VORICONAZOLE
• Active vs C. neoformans, Trichosporon
• Broadly active vs Aspergillus including A. terreus
• Reasonably active for dimorphic fungi, but less so for Sporothrix
• Active vs Fusarium
• Cidal for Candida, static for Aspergillus (like caspofungin)
• ZYGOMYCETES ARE NOT SUSCEPTIBLE
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VORICONAZOLE: DETAILS
• 90% oral absorption, Tmax 2 h, take on empty stomach
• Nonlinear kinetics
• SS Vd 4.6 L/kg; CSF conc 29-68% of serum
• Wide interpatient variability in plasma concentrations
• Elimination t½ 6 hours
• Metabolites eliminated in the urine; <5% of drug eliminated unchanged. Major metabolite: N-oxide.
• Decrease dose in hepatic failure
• Obesity: use total body weight
• Weird side effect: visual disturbances
• Dose: 6 mg/kg IV q12h x2 doses, then 4 mg/kg IV q12h (200 mg po q12h when appropriate to switch)
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VORICONAZOLE AND DRUG INTERACTIONS
• Substrate and inhibitor of multiple cytochrome P450 enzymes (CYP2C9, CYP2C19, CYP3A4)
• 2C19 is the major metabolizing enzyme; 3A4 is less important
• 2C19 exhibits genetic polymorphism (e.g. 15-20% of Asians are expected to be slow metabolizers)
• Voriconazole as the object drug: avoid rifampin and ritonavir
• Vori as the precipitant drug: lots more to avoid. For example, sirolimus is contraindicated, but CSP and tacrolimus are ok if their doses are lowered.
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Canuto MM & Rodero FG. The Lancet Infect Dis 2002; 2: 550
CASPOFUNGIN (CANCIDAS)
our first echinocandin; “penicillin for fungi”
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CLINICAL USE OF CASPOFUNGIN
• May become the drug of choice for invasive candidiasis, candidemia
• Synergistic with voriconazole in vitro; in vivo data are scant but supportive for certain mold infections such as Aspergillus
• Most common toxicities: infusion-related adverse effects, headache
• Increased LFTs, especially in patients receiving cyclosporine (less with micafungin?)
• Dose: 70 mg IV on day 1, then 50 mg daily (reduced for hepatic insufficiency). Infused over 1 hour in non-dextrose containing solution.
• Cost: $300-400/day
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POSACONAZOLE (SCHERING-PLOUGH)
• New broad-spectrum triazole• Active vs Candida, Trichosporon,
Aspergillus, Fusarium, Mucor, Rhizopus• Vd 6 L/kg; 97-99% protein bound; T1/2 25
hr; glucuronidated, metabolites excreted in feces
• Inhibits CYP3A4• Common ADR: fever, GI• Dose: 200 mg po qid or 400 mg po bid• Oral BA 4x with high fat meal; susp is
35% more bioavailable than capsules; split dosing improves absorption
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IMPORTANT USES OF ANTIVIRAL DRUGS
• INFLUENZA
• HEPATITIS B AND C
• HERPESVIRUS (HSV, VZV, CMV)
• HIV (outside our scope for today)
• MISCELLANEOUS (e.g. ribavirin for RSV)
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INFLUENZA DRUGS ARE SOMETIMES USEFUL IN OUTBREAK SITUATIONS
Drug Treatment Prophylaxis
Amantadine 1 year 1 year
Rimantadine 13 years 1 year
Oseltamivir 1 year 13 years
Zanamivir (inhaled)
7 years Not approved•Not a substitute for vaccination•Amantadine and rimantadine are ineffective for influenza B•Treatment should begin within 2 days of symptom onset•Serious influenza-related complications are not prevented
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TREATMENT OF HEPATITIS B
• ACUTE– No therapy recommended
• CHRONIC– IFN-2b 5mu sq qd (or 10 mu sq tiw)
x16 weeks– Lamivudine (Epivir) 100 mg po qd
x1 year or more– Adefovir (Hepsera) 10 mg po qd
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TREATMENT OF HEPATITIS C
• ACUTE– PEG-IFN + ribavirin as below, but
remains controversial
• CHRONIC– PEG-IFN-2a (Pegasys) 180 mcg sq
q-week or -2b (Peg-Intron) 1.5 mcg/kg sq q-week PLUS oral ribavirin (genotype 1: 400 mg qam + 600 mg qpm if <75 kg, 600 mg po bid if >75 kg; genotype 2 or 3, 400 mg po bid regardless of weight)
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DRUGS FOR HERPESVIRUS
• Herpes simplex virus (HSV), varicella-zoster virus (VZV)– Acyclovir– Famciclovir– Valacyclovir
• Cytomegalovirus (CMV)– Ganciclovir– Valganciclovir– Foscarnet (toxic, avoid)– Cidofovir + probenecid (toxic, avoid)
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THANK YOU FOR ATTENDING MY PRESENTATIONS THIS QUARTER!
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