THERAPY USING ANTIFUNGALS AND ANTIVIRALS

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THERAPY USING ANTIFUNGALS AND ANTIVIRALS

• Douglas Black, Pharm.D.
• Associate Professor
• School of Pharmacy
• University of Washington
• dblack_at_u.washington.edu

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CLASSIFICATION OF FUNGI
Yeasts Dimorphic fungi Molds
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. albicans
• C. tropicalis
• C. parapsilosis
• C. kefyr
• C. glabrata
• C. krusei
• C. guillermondii
• C. lusitaniae

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LONGITUDINAL STUDIES A TEN-YEAR FUNGEMIA SURVEY
Krcmery V Jr. et al. DMID 2000 36 7. Slovak
Republic
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HISTORY OF ANTIFUNGAL DRUGS
1950s Nystatin Amphotericin B Griseofulvin
1960s Miconazole Clotrimazole
1980s Ketoconazole
1970s Flucytosine
1990s Fluconazole Itraconazole caps Itraconazole
soln Terbinafine Lipid Ampho
Micafungin Anidulafungin Posaconazole
2000s Caspofungin Voriconazole
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AMPHOTERICIN B DEOXYCHOLATE

• Good
• Fungicidal
• Broad spectrum
• Relatively inexpensive

• Not so good
• A few holes in coverage
• Complex pharmacokinetics
• Significant IRAEs
• Nephrotoxicity
• -glomerular
• -tubular
• Hematologic toxicity
• Difficult 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 DOSE
• AMB (1 mg/kg)
• ABLC (5 mg/kg)
• L-AMB (5 mg/kg)

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FLUCYTOSINE (5-FC)
CP
CD
Intracellular 5-FC
5-FC
5-FU
UMP PPase
UPRTase
5-fluorouridine monophosphate (FUMP)
5-fluorodeoxyuridine monophosphate
(F-dUMP) thymidylate synthase inhibitor inhibits
DNA synthesis
phos x2
5-fluoro-UTP (FUTP) incorporated into
RNA disrupts protein synthesis
ENZYMES CP cytosine permease CD cytosine
deaminase UPRTase uracil phosphoribosyl
transferase UMP Ppase UMP pyrophosphorylase
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A SUMMARY OF FLUCYTOSINE

• Good
• Activated by fungal enzymes
• Unique mechanism of action
• Excellent tissue penetration
• Simple renal elimination
• Serum concentrations can be monitored

• Not so good
• Somewhat narrow spectrum
• Frequent dosing, large capsules
• Bone marrow suppression
• Hepatotoxicity
• Secondary resistance
• Expensive (about 6.30 per 500mg capsule)

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AZOLE ANTIFUNGALS AVAILABLE IN THE US

• Four systemic drugs
• Ketoconazole (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)

• Toxicity
• ketoconazole gt itraconazole gt fluconazole
• DI potential
• ketoconazole gt itraconazole gt fluconazole
• Pregnancy
• all topical azoles are considered safe (avoid
  systemic administration)

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ANTICANDIDAL ACTIVITY OF VORICONAZOLE
MIC90

• C. albicans 0.015-0.5
• C. parapsilosis 0.015-0.125
• C. kefyr 0.015
• C. tropicalis 0.03-1
• C. glabrata 0.25-4
• C. krusei 0.25-2
• C. lusitaniae 0.5

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 lt5 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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CASPOFUNGIN (CANCIDAS)
our first echinocandin penicillin for fungi
Canuto MM Rodero FG. The Lancet Infect Dis
2002 2 550
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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
  lt75 kg, 600 mg po bid if gt75 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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