THERAPY USING ANTIFUNGALS AND ANTIVIRALS

Douglas Black, Pharm.D.Associate ProfessorSchool of Pharmacy

University of Washingtondblack@u.washington.edu

CLASSIFICATION OF FUNGI

YeastsDimorphic

fungiMolds

Candida Blastomyces Aspergillus

Cryptococcus

Coccidioides Fusarium

Trichosporon

Histoplasma Rhizopus

Sporothrix Mucor

Absidia

Pseudallescheria

(Scedosporium)

MOST COMMONLY ISOLATED SPECIES OF CANDIDA

C. albicansC. tropicalisC. parapsilosis C. kefyrC. glabrata C. kruseiC. guillermondiiC. lusitaniae

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

HISTORY OF ANTIFUNGAL DRUGS

1950sNystatin

Amphotericin BGriseofulvin

1960sMiconazole Clotrimazole

1970sFlucytosine

1980sKetoconazole

1990sFluconazole

Itraconazole capsItraconazole soln

TerbinafineLipid Ampho

2000sCaspofunginVoriconazole

MicafunginAnidulafunginPosaconazole

AMPHOTERICIN B DEOXYCHOLATE

Good FungicidalBroad spectrumRelatively

inexpensive

Not so goodA few holes in

coverageComplex

pharmacokineticsSignificant IRAEsNephrotoxicity

-glomerular-tubular

Hematologic toxicityDifficult dosing

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

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

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

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)

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

TOXICITIES AND DRUG INTERACTION POTENTIAL (EXCEPT

VORI)

Toxicityketoconazole > itraconazole > fluconazole

DI potential ketoconazole > itraconazole >

fluconazole

Pregnancyall topical azoles are considered safe (avoid systemic administration)

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

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

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)

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.

Canuto MM & Rodero FG. The Lancet Infect Dis 2002; 2: 550

CASPOFUNGIN (CANCIDAS)

our first echinocandin; “penicillin for fungi”

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

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

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)

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

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

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)

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)

THANK YOU FOR ATTENDING MY PRESENTATIONS THIS QUARTER!