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A. Cutaneous / Topical [2]navigator

  1. Nystatin (Mycostatin®)
    1. Like amphotericin, binds to cell wall ergosterol and causes fungal lysis
    2. Powders, creams, oral suspensions available
  2. Topical Imidazoles
    1. Inhibit ergosterol synthesis, generally fungistatic
    2. Clotrimizole (Lotrimen®) - topical, also for vaginitis and thrush, various formulations
    3. Miconazole (Mycotin®) - athlete's foot, other tinea, "jock itch"
    4. Tioconazole and terconazole have activity against non-albicans Candidal strains
    5. Econazole (Spectazole®)
  3. Benzyl and Allylamines
    1. Inhibit ergosterol synthesis; may be fungicidal rather than fungistatic
    2. Naftifine (Naftin®) - qd application for tinea pedis, others; treat for 4 weeks
    3. Butenafine (Mentax®) - qd application x 4 weeks for all forms of tinea, low relapse [2]
    4. Terbinafine (Lamisil®) - athlete's foot, other tinea, rapidly effective (oral available)
  4. Ciclopirox (Loprox®)
    1. Antifungal and anti-inflammatory activity
    2. Good skin penetration, once daily
  5. These agents are sometimes used with low or intermediate potency topical steroids

B. Topical Steroidal Anti-Inflammatory Agents navigator

  1. Very large number of agents of varying strengths
  2. Triamcinolone ointment
  3. Mometasone (Elocon®)
  4. Fluorinated steroids - too potent potent for this application; avoid
  5. Caution when using these agents
    1. May exacerbate fungal infection if used without antifungal agent
    2. Limit use to 2-3 days
    3. Excellent symptomatic improvement

C. Systemic Anti-Fungal Agents [5,21]navigator

  1. Amphotericin B deoxycholate (ABD): various formulations
  2. 5-Fluorocytosine (5-FC, Flucytosine®)
    1. Inhibits DNA synthesis
    2. Typically used in combination with ABD [33]
  3. Azoles - inhibit sterol synthesis by Cytochrome P450 enzymes (fungal >> human)
    1. Fluconazole (Diflucan®)
    2. Itraconazole (Sporanox®)
    3. Ketoconazole (Nizoral®)
    4. Voriconazole (Vfend®)
    5. Posaconazole (Noxafil®)
  4. Terbinafine (Lamasil®): 250mg po bid for onychomycosis (athlete's foot and others)
  5. Echinocandins [4]
    1. Caspofungin (Cancidas®)
    2. Micafungin (Mycamine®)
    3. Anidulafungin (Eraxis®)
  6. Griseofulvin

D. Amphotericin B Deoxycholate (ABD) [21,27]navigator

  1. Properties
    1. Most potent anti-fungal now in use
    2. Binds to fungal membrane steroid, ergosterol, and causes holes in fungal membrane
    3. Active against almost all pathogenic fungi
    4. May be used in combination with 5-FC, but with increased side effects
  2. Formulations
    1. Standard ABD
    2. Lipid complex ABD formulation (Abelcet®)
    3. Liposomal ABD (AmBisone®)
    4. Colloidal Disperson (Amphotec®)
  3. Dosing Standard ABD
    1. Initial test dose 1mg, then 0.5mg/kg (no need for gradual increase in dose) over 4-6 hrs
    2. After 24 hours, increase to full dose
    3. Full dose is usually 0.6mg/kg for candida
    4. Full dose 1-1.5mg/kg for Aspergillus
    5. Full dose 0.7mg/kg for Histoplasmosis
    6. ABD + 5-FC had most rapid rate of clearance of cryptococcal meningitis in patients with HIV, compared with ABD alone, ABD+fluconazole, or ABD+5-FC+fluconazole [33]
    7. Administration over 24 hours is associated with reduced side effects AND mortality [18]
    8. Strongly consider administering full dose ABD over 24 (versus ~4) hours
    9. Premedication with hydrocortisone
    10. If patient has rigors, treat with iv meperidine (Demerol®)
    11. Use meperidine with caution in patients with seizure disorders or renal insufficiency
  4. Side Effects of Standard Formulation
    1. Venous Sclerosis
    2. Rental Tubular Effects: hypokalemia, hyperkalemia, hypomagnesemia
    3. Nephrotoxicity (see below)
    4. Thrombophlebitis
    5. Fever, chills, nausea and vomiting - nearly all patients for first few doses
    6. Anemia
    7. Rash
    8. Chills / Rigors
    9. Prolonged administration over 24 hours associated with reduced side effects
    10. Liposomal formulations also have reduced side effects
  5. Nephrotoxicity [17]
    1. Ranges from 10-80% in most studies
    2. Tubular acidosis, mild azotemia, chronic renal failure can occur
    3. Significant renal failure almost always in patients with baseline renal insufficiency
    4. Cyclosporine or amikacin (or other aminoglycosides) can increase nephrotoxicity
  6. Liposomal Amphotericin Formulations
    1. Liposomal and lipid complex formulations are available
    2. Less nephrotoxic and less infusion related toxicity compared with standard
    3. Liposomal ABD is less toxic than lipid complex formulation
    4. As effective, better tolerated, safer than standard ABD in fever and neutropenia [12]
    5. Liposomal ABD 3mg/kg/d more effective, better tolerated for histoplasmosis in AIDS [26]
    6. FDA approved for patients intolerant of and/or not responding to standard amphotericin
    7. Lipid complex dosed 5mg/kg daily (Abelcet®)
    8. Liposomal (AmBisome®) ABD 3 or 5mg/kg daily
    9. More expensive than standard ABD

E. Fluconazole (Diflucan®)navigator

  1. Potent and well tolerated oral (and iv) anti-fungal triazole
  2. Specific for fungal C14-a-demethylase which blocks lanosterol conversion to ergosterol
  3. Dose is100mg-800mg po qd (may be divided) depending on organism
  4. Well tolerated, good oral absorption
    1. Hepatic transaminase elevation is uncommon side effect
    2. Rash or Stevens Johnsons Syndrome has been reported
  5. Excellent central nervous system penetration
  6. Fungal Urinary Tract Infections (UTI)
    1. Excellent for fungal UTIs due to sensitive organisms
    2. Most of these are due to Candida (C.) albicans
    3. However, C. tropicalis and C. glabrata yeasts are often resistant
    4. Dose is usually 200mg po qd x 5 days
  7. For fungal prostatitis, dose is 200mg qd for14-28 days
  8. Vulvovaginal Candidiasis
    1. Candidal infection common, particularly after antibiotics for UTI
    2. Fluconazole 150mg x 1 very effective in most patients
    3. In patients with recurrent candidiasis, fluconazole 150mg weekly for 6 months reduces recurrence from 72% with placebo to 10% [7]
  9. Candidemia [1]
    1. Effective in many non-neutropenic patients with candidemia
    2. Better tolerated than amphotericin
    3. Dose 400mg/d versus amphotericin 0.5-0.6mg/kg/d x 14d after last positive blood culture
    4. ~14% failure rates for both agents
    5. Most patients had renal failure, gastrointestinal problems (often on parenteral nutrition), or non-hematologic cancer
    6. Toxicity was higher with amphotericin but had slightly more successful treatment
    7. Mortality was not statistically different for amphotericin (40%) versus fluconazole (33%)
    8. Role in treatment of non-albicans Candida species is less clear
    9. ~50% of C. glabrata isolates are flunconazole resistant [24,25]
    10. Increasing use of amphotericin B for ~4 days followed by oral fluconazole for candidemia [8]
    11. Empirical fluconazole in intensive care unit patients who have not responded to antibiotics should reduce mortality [34]
    12. However, empirical fluconazole did not benefit non-neutropenic intensive care patients with fevere despite antibacterial therapy [43]
    13. Prophylactic fluconaozle 3-6mg/kg qd in preterm neonates reduced invasive fungal infections and fungal colonization without significant side effects [42]
  10. Neutropenic Patients
    1. Voriconazole or posaconazole (see below) are generally prefered over fluconazole in neutropenic patients
    2. Reduces infection risk in patients undergoing blood cell transplantation [23]
    3. Prophylaxis with fluconazole in leukemia or transplant patients increases risk of colonization and infection with C. glabrata
    4. Posaconazole superior to fluconazole for prophylaxis in severe graft-versus-host disease (GVHD) and in acute myeloid leukemia (AML) patients receiving chemotherapy [9,10]
  11. Other Activities [1]
    1. High dose 400mg po bid for blastomycosis
    2. High dose 200-400mg po bid for coccidioidomycosis [14]
    3. Cryptococcus responds to 400mg po qd (also used for chronic suppression in HIV)
    4. High dose 400mg po bid for histoplasmosis
    5. 200mg po qd x 6 weeks for cutaneous Leishmania major [22]
  12. Drug Interactions [13]
    1. Mild increase in cyclosporine levels
    2. Phenytoin (Dilantin®) toxicity
    3. Warfarin - enhanced anticoagulation is very prominent
    4. Astemizole (Hismanal®) - increased QTc interval, risk for Torsades de Pointes
    5. Cisapride (Propulsid®) - increased QTc interval, risk for Torsades de Pointes
    6. Avoid with HMG CoA reductase inhibitors - increased risk rhabdomyolysis
    7. Mainly related to inhibition of Cytochrome P450 29C

F. Itraconazole (Sporanox®) [3]navigator

  1. Broad spectrum oral anti-fungal agent; also available as IV agent
  2. Dosage
    1. Usual dose is 200-400mg po qd
    2. Dose is often doubled in patients with HIV and other immunodeficiencies
  3. Treatment Efficacy [1]
    1. >95% effective 200mg po qd-bid for Histoplasmosis and Blastomycosis
    2. Active against Aspirgillus in ~75% of patients, but clinical significance is unclear
    3. Excellent against Sporotrichosis and for onychomycosis (especially feet) due to fungus
    4. Second line for candida, coccidiodomycosis, and cryptococcus
    5. Slightly more effective at 200mg bid for coccidiomycosis than fluconazole [14]
    6. Itraconazole 200mg x 2 in first 24 hours, then 200mg daily, is as effective as, and far better tolerated than, standard ABD in fever and neutropenia [16]
    7. Itraconazole 200mg po bid (or 200mg IV qd) is more effective than fluconazole 400mg po or IV qd through day 100 post-allogeneic transplant (infections 9% versus 25%) [31]
    8. Treatment and prophylaxis against Penicillium marneffei [11]
    9. Prophylaxis in chronic granulomatous disease (CGD) reduces risk of serious and superficial infections [32]
    10. No efficacy in mucormycosis
    11. Poor CSF penetration
  4. Drug Interactions [13]
    1. Gastric acidity required for absorption; H-2- and Acid Pump- blockers reduce levels
    2. Rifampin, Phenytoin (Dilantin®), Carbamazepine (Tegretol®) decreased levels
    3. Inhibts P450 3A4 enzyme in liver and increases levels of many drugs
    4. Increases levels of cyclosporine, tacrolimus, digoxin, cisapride (Propulsid®), others
    5. Increases levels of benzodiazepines midazolam (Versed®) and triazolam (Halcion®)
    6. Serious arrhythymias due to QTc prolongation with terfenidine (Seldane®), astemizole (Hismanal®), cisapride (Propulsid®); these agents have been removed from market
  5. Liver function tests should be monitored with long term use [32]

G. Voriconazole (Vfend®) [19,20,27,28,38]navigator

  1. Second generation triazole
  2. Broad spectrum agent with good antifungal activity:
    1. Aspergillus - has largely replaced ABD
    2. Fusarium ssp.
    3. Scedosporium
    4. Candida
  3. Good efficacy in vivo given orally or parenterally
    1. Parenteral: 6mg/kg IV q12 hours x 2 doses, then 4mg/kg IV q12 hours
    2. Oral: 200mg (>40kg) or 100mg (<40kg) po q12 hours
    3. Maintain oral dosing as long as required
  4. Efficacy
    1. Nearly as good as liposomal ABD in neutropenic patients with persistent fever [36]
    2. Superior response and survival in primary invasive aspirgillosis compared with ABD [27]
    3. Unclear if voriconazole is as effective as caspofungin [36]
    4. Voriconazole (Vfend® IV then PO) is as effective as amphotericin followed by fluconazole for candidemia in non-neutropenic patients [8]
  5. Considerably improved tolerability compared with ABD
    1. Transient visual changes (~20%) and hallucinations (~5%) are main side effects
    2. Overall well tolerated with minimal infusion-related and kidney toxicities
  6. FDA approved for primary treatment of aspirgillosus, fusarium, scedosporium
  7. Also approved for candidal esophagitis and candidemia

H. Posaconazole (Noxafil®) [6]navigator

  1. Oral azole antifungal, similar to itraconazole
  2. Approved for prevention of Candida and Aspergillus in severe immunocompromise
  3. Efficacy demonstrated against zygomycosis, fusariosis, histoplasmosis, cocidiomycocis
  4. Also active against cryptococcal meningitis
  5. Efficacy in resistant infections
  6. Superior to fluconazole for preventing invasive aspergillosis and reducing fungal-related deaths in patients with allotransplant and severe GVHD [9]
  7. Superior to fluconazole and itraconazole for prophylaxis of fungal infections and overall mortality in patients with AML or myelodysplastic syndrome receiving chemotherapy [10]
  8. Inhibitor of CYP3A4 with expected drug interactions
  9. Dose is 200mg tid for prophylaxis, always taken with full meal or liquid nutritional supplement
  10. Dose is 200mg x 1, followed by 100mg qd x 13d for oropharyngeal candidiasis
  11. Invasive fungal infections treated with 200mg qid until improvement, then 400mg bid
  12. Relatively well tolerated; nausea, vomiting, diarrhea, abdominal pain, headache do occur

I. Ketoconazole (Nizoral®) [1]navigator

  1. Oldest and weakest of the oral anti-fungals
  2. Dose is typically 200-800mg per day, usually as second or third line therapy
  3. Dependent on acid pH for absorption
  4. Side effects
    1. Common nausea, vomiting, and pruritis
    2. Mild hepatic toxicity occurs as well
    3. Adrenal suppression may occur, particularly with concurrent glucocorticoids
  5. Strongly inhibits CYP 3A4, with drug interactions similar to itraconazole [13]

J. Echinocandins [4,15]navigator

  1. Large amphiphilic cyclic hexapeptides
  2. Block synthesis of ß(1,3)-D-glucan found in fungal cell wall
  3. Specifically block ß(1,3)-D-glucan synthase
  4. Spectrum
    1. Candida species including all non-albicans species [29]
    2. Aspirgillosis including that unresponsive to amphotericin or itraconazole
    3. Pneumocystis carinii - only cyst stage
    4. Some activity against coccidioides, blastomyces, histoplasma, scedosporium, paeilomyces
    5. Little activity against cryptococcus, fusarium, mucormycetes (zygomycetes), trichosporon
  5. Caspofungin (Cancidas®) [12,15]
    1. Generally well tolerated
    2. Dose is 70mg on day 1, 50mg thereafter, intravenous infusion over 1 hour
    3. Fever, rash, nausea, vomiting and phlebitis are side effects
    4. Reduce dose to 35mg maintenance per day with hepatic failure
    5. No dose adjustment for renal failure
    6. Caspofungin is as effective and far better tolerated than amphotericin for neutropenic or non-neutropenic patients, including non-albicans species [30]
    7. Caspofungin is clearly as (possibly more) effective as and is better tolerated than liposomal ABD in persistent fever and neutropenia [35]
    8. Caspofungin is a very good replacement for liposomal ABD in persistent fever and neutropenia [36]
  6. Micafungin (Mycamine®) [37]
    1. Approved for IV treatment of esophageal candidiasis and candidal prophylaxis
    2. Active in vitro against most Candida and Aspergillus species
    3. Active in vitro against fluconazole-resistant Candida and non-albicans Candida
    4. As effective as liposomal amphotericin B, with fewer side effects, in candidemia and invasive candidosis, including across all non-albicans species [40]
    5. Generally well tolerated: fever, headache, nausea, vomiting, diarrhea, liver abnormalities
    6. Dose is 50mg/day for prophylaxis, 150mg/day for treatment, IV over 1 hour
  7. Anidulafungin (Eraxis®) [39]
    1. Approved for IV treatment of esophageal candidiasis, candidemia, other complicated candida infections
    2. Active in vitro against most Candida and Aspergillus species
    3. Active in vitro against fluconazole-resistant Candida and non-albicans Candida
    4. Dose for esophageal candidiasis is 100mg IV day 1, then 50mg daily for 14 days
    5. Dose for complex candida infections is 200mg on day 1, then 100mg dailyfor 14 days after the last positive candida culture
    6. Invasive candidiasis treated for 10 days with IV anidulafungin (75% success) is superior to fluconazole (60% success) in mainly nonneutropenic patients [41]
    7. No clear benefits over other echinocandins

K. Griseofulvin (Fulvicin®, Grisactin®, Grifulvin V®, others)navigator

  1. Fungistatic for various dermatophytes including
    1. Microsporum
    2. Epidermophyton
    3. Trichophyton
  2. No effect on other fungi (or any bacteria)
  3. Inhibits fungal mitosis by interacting with polymerized microtubules
  4. Besides binding to polymerized tubulin, may also bind to microtubule associated proteins
  5. Dose is 250 mg qid or bid, or 500mg po bid for adults
  6. Children's dose is 15mg/kg
  7. Duration is 1 month for scalp and hair ringworm, 6-12 months for onycholysis
  8. Side effects: headache (15%), peripheral neuritis, liver function abnormalities
  9. Induces hepatic metabolism (including warfarin)
  10. Generally not recommended since more effective agents are now available

References navigator

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  2. Butenafine. 1997. Med Let. 39(1004):63 abstract
  3. Itraconazole. 1994. Med Let. 36(916):16
  4. Denning DW. 2003. Lancet. 362(9390):1142 abstract
  5. Terbinafine. 1996. Med Let. 38(967):10
  6. Posaconazole. 2006. Med Let. 48(1248):93 abstract
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  8. Kullberg BJ, Sobel JD, Ruhnke M, et al. 2005. Lancet. 366(9495):1435 abstract
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  13. Gregg CR. 1999. Am J Med. 106(2):227 abstract
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  15. Caspofungin. 2001. Med Let. 43(1108):58 abstract
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  17. Harbarth S, Pestotnik SL, Lloyd JF, et al. 2001. Am J Med. 111(7):528 abstract
  18. Eriksson U, Seifert B, Schaffner A. 2001. BMJ. 322:579 abstract
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  35. Walsh TJ, Teppler H, Donowitz GR, et al. 2004. NEJM. 351(14):1391 abstract
  36. Klastersky J. 2004. NEJM. 351(14):1445 abstract
  37. Micafungin. 2005. Med Let. 47(1211):51 abstract
  38. Patterson TF. 2005. Lancet. 366(9490):10132 abstract
  39. Anidulafungin. 2006. Med Let. 48(1235):43 abstract
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