Antifungal Agents
Factors increasing incidence and severity of human fungal infections:
Increased use of broad spectrum antibiotics
HIV epidemic
cancer chemotherapy protocols
Examples of increased incidence: Candida albicans -- fourth most common organism isolated from blood (USA)
Most fungi are completely resistant to conventional antibacterial agents
Significant Development: availability of relatively non-toxic, orally administered, azole drugs.
Concern: evolution of azole-resistant fungi
Three Antifungal Drug Categories:
Systemic drugs: systemic infection (oral or parenteral route of administration)
Mucocutaneous infections: oral route of administration
Mucocutaneous infections: topical
Amphotericin B: (Fungizone, Amphotec)
Produced by Streptomyces nodosus
Antifungal Activity:
Broadest spectrum of antifungal action
Activity against yeasts:
Candida albicans
Candida neoformans
Activity against endemic mycoses:
Histoplasma capsulatum
Blastomyces dermatitidis
Coccidiodes immitis
Pathogenic molds
Aspergillus fumigatus
Mucor
Pharmacokinetics: Amphotericin B (Fungizone, Amphotec)
Poorly absorbed from the GI tract
Oral administration: useful for gastrointestinal luminal fungal infections (non-systemic)
intravenous administration -- to treat systemic infection
> 90% protein-bound
Mainly metabolized -- some excreted by the kidney
Poor cerebral spinal fluid levels following IV administration:
Intrathecal drug administration may be required in some cases of fungal meningitis
Mechanism of Action: Amphotericin B (Fungizone, Amphotec)
In fungi the major sterol: ergosterol (mammalian cell membrane: major sterol-- cholesterol
Amphotericin B binds to ergosterol -- changing cell permeability
Amphotericin B induced pores resulted in fungal cell death through:
Ion leakage
Loss of macromolecules
Amphotericin B binding to human membrane sterols occurs:
Possible basis for drug toxicity
Adverse Effects: Amphotericin B (Fungizone, Amphotec)
Common Reactions Associated with intravenous Route of Administration:
fever |
muscle spasms |
headache |
chills |
hypotension |
vomiting |
Delayed Toxicity:Amphotericin B
Renal damage -- most significant toxic effect; Frequency -- nearly all patients
May require dialysis
Reversible component: pre-renal kidney failure (reversible)
Irreversible component: renal tubular necrosis
Renal toxicity associated with:
Renal tubular acidosis
Potassium loss
Magnesium loss
Less renal damage with concurrent sodium (saline infusion) administration with amphotericin B
Abnormal liver function tests:(occasional)
Reduced erythropoietin production: (associated with renal tubular cell damage)
Convulsions: associated with intrathecal amphotericin B administration.
Clinical Use: amphotericin B (Fungizone, Amphotec)
Drug of choice for nearly all life-threatening fungal infections.
Initial induction treatment -- then one of the newer azole drugs (ketoconazole (Nizoral), itraconazole (Sporanox), fluconazole (Diflucan))
Amphotericin B treatment induction:
Important in:
Immunosuppressed patients
Severe fungal pneumonia
Cryptococcal meningitis (altered mental status present)
Long-term antifungal treatment may beer acquired (azole maintenance therapy)
May be used in neutropenic cancer patients remaining febrile despite management using broad-spectrum antibiotics.
Intrathecal treatment: fungal meningitis (other therapies preferred, in part due to difficulty maintaining CSF access and poor patients tolerance)
Local Administration:
Mycotic corneal ulcers (topical or subconjuctival injection)
Kerititis (topical or subconjuctival injection)
Fungal arthritis (joint injection)
Candiduria: bladder irrigation (no systemic toxicity)
Flucytosine (Ancobon)
Introduction:
Water-soluble pyrimidine analog (related to flurouracil)
Narrower spectrum infection compared amphotericin B
Pharmacokinetics: Flucytosine (Ancobon)
Penetrates well into body fluid compartments -- including the CSF
Eliminated by glomerular filtration (may be removed by hemodialysis)
Toxicity may occur with reduced renal function
Toxicity more likely to occur in AIDS patients
Mechanism of Action: Flucytosine (Ancobon)
Uptake by fungal cells mediated by cytosine permease
Converted intracellularly to:
5-fluorouracil (5-FU)
5-fluorodeoxyuridine monophosphate (FdUMP)-- DNA synthesis inhibitor
Fluorouridine triphosphate (FUTP) -- RNA synthesis inhibitor
Synergism with amphotericin B
Possible mechanism: increased flucytosine penetration through amphotericin B-damaged fungal cell membranes
Synergism with azoles (undefined mechanism)
Resistance: rapidly develops and monotherapy
probable mechanism: altered flucytosine metabolism
Adverse Effects: Flucytosine (Ancobon)
Probably due to toxic, antineoplastic metabolites (5-FU)
Most common toxicities:
Anemia
Leukopenia
Rhrombocytopenia
Narrow therapeutic window (toxicity of higher levels; rapid development of resistance at lower, sub-therapeutic levels
Clinical Use: Flucytosine (Ancobon)
Not used in monotherapy (rationale: synergism with other drugs; avoidance of resistance)
Effective against:
Cryptococcus neoformans
Some Candida species
Chromoblastomycosis
In combination with amphotericin B for: cryptococcal meningitis
In combination with a terconazole for: chromoblastomycosis
Major advantage-Azoles: oral Route of Administration, relatively nontoxic
Synthetic compounds-- classification depending on the number of nitrogen atoms in the five-membered azole ring
Imidazoles
Ketoconazole (Nizoral)
Miconazole (topical) (Monistat)
Clotrimazole (topical) (Mycelex)
Triazoles
Itraconazole (Sporanox)-- systemic treatment
Fluconazole (Diflucan)-- systemic treatment
Decreased ergosterol synthesis due to inhibition of fungal cytochrome P450 enzymes
Specificity: -- these drugs have higher affinity for fungal compared to human cytochrome P450 enzymes
Triazoles -- higher specificity (fewer side effects)
Imidazoles -- lower specificity (more side effects)
Resistance: -- multiple mechanisms; increased incidence of resistance
Many Candida species
Cryptococcus neoformans
Endemic mycoses:
Blastomycoses
Coccidiodomycosis
Hstoplasmosis
Dermatophytes
Aspergillus:itraconazole
Pseudallesceria boydii (amphotericin-resistant organism)
Relatively nontoxic
Most common: minor gastrointestinal upset
Very rare: hepatitis
Drug Interactions: Azoles-- drug interactions due to effects on cytochrome P450 enzyme systems
Sheppard,D. and Lampiris, H.W., Antifungal Agents, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 780-786
Bennett, J.E. Fungal Infections (Section 15: Infectious Diseases), In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., andBraunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp. 1148-1163