THERAPY USING ANTIFUNGALS AND ANTIVIRALS Douglas Black, Pharm.D. Associate Professor School of Pharmacy University of Washington dblack@u.washington.edu CLASSIFICATION OF FUNGI Yeasts Candida Cryptococcus Trichosporon Dimorphic fungi Blastomyces Coccidioides Histoplasma Sporothrix Molds Aspergillus Fusarium Rhizopus Mucor Absidia Pseudallescheria (Scedosporium) MOST COMMONLY ISOLATED SPECIES OF CANDIDA C. albicans C. tropicalis C. parapsilosis C. kefyr C. glabrata C. krusei C. guillermondii C. lusitaniae
LONGİTUDİNAL STUDİES: A TEN-YEAR FUNGEMİA SURVEY 120 100 80 albicans % non-albicans % 60 40 20 0 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 Krcmery V Jr. et al. DMID 2000; 36: 7. Slovak Republic HISTORY OF ANTIFUNGAL DRUGS 1950s Nystatin Amphotericin B Griseofulvin 1960s Miconazole Clotrimazole 1970s Flucytosine 1980s Ketoconazole 1990s Fluconazole Itraconazole caps Itraconazole soln Terbinafine Lipid Ampho 2000s Caspofungin Voriconazole Micafungin Anidulafungin Posaconazole 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
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 DOSE AMB (1 mg/kg) ABLC (5 mg/kg) L-AMB (5 mg/kg) 600 500 400 300 200 100 0 AMB ABLC L-AMB FLUCYTOSINE (5-FC) 5-FC CP Intracellular 5-FC CD UPRTase 5-FU UMP PPase 5 -fluorouridine monophosphate (FUMP) phos x2 5 -fluorodeoxyuridine monophosphate (F-dUMP dump) thymidylate synthase inhibitor inhibits DNA synthesis 5 -fluoro-utp (FUTP) incorporated into RNA disrupts protein synthesis ENZYMES: CP = cytosine permease CD = cytosine deaminase UPRTase = uracil phosphoribosyl transferase UMPPpase= UMPpyrophosphorylase
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) 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 TOXICITIES AND DRUG INTERACTION POTENTIAL (EXCEPT VORI) Toxicity ketoconazole > itraconazole > fluconazole DI potential ketoconazole > itraconazole > fluconazole Pregnancy all topical azoles are considered safe (avoid systemic administration)
ANTICANDIDAL ACTIVITY OF VORICONAZOLE MIC 90 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 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, T max 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 t ½ 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. CASPOFUNGIN (CANCIDAS) our first echinocandin; penicillin for fungi Canuto MM & Rodero FG. The Lancet Infect Dis 2002; 2: 550 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 Amantadine Treatment 1 year Prophylaxis 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-α2b 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-α2a (Pegasys) 180 mcg sq q- week or -α2b (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), varicellazoster virus (VZV) Acyclovir Famciclovir Valacyclovir Cytomegalovirus (CMV) Ganciclovir Valganciclovir Foscarnet (toxic, avoid) Cidofovir + probenecid (toxic, avoid)
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