2. Antifungal Drugs
• Human fungal infections have increased dramatically in recent
years, owing mainly to advances in surgery, cancer treatment, and
critical care accompanied by increases in the use of broad-spectrum
antimicrobials and the HIV epidemic. These changes have resulted
in increased numbers of patients at risk for fungal infections.
• Antifungal drugs are used for superficial and deep (systemic) fungal
infections.
• Important antibiotics: amphotericin-B, griseofulvin
• Novel antifungal agent: Terbinafine
• Recently added drug: Echinocandins
4. Antifungal Drugs- Polyene antibiotics
• Polyene is derived from their highly double-bonded structure.
Amphotericin B is described as the prototype.
• Prototype: Amphotericin B (AMB)
• Source: Streptomyces nodosus
• Chemistry:
• Amphotericin B is an amphoteric polyene macrolide (polyene =
containing many (seven) double bonds; macrolide = containing a
large lactone ring of 12 or more atoms).
• It is nearly insoluble in water and is therefore prepared as a
colloidal suspension of amphotericin B and sodium desoxycholate
for intravenous injection. Several new formulations have been
developed in which amphotericin B is packaged in a lipid-associated
delivery system (Liposomal Amphotericin B)
5. Antifungal Drugs- Polyene antibiotics
• The polyenes have high affinity for ergosterol present in fungal cell
membrane.
• This Polyenes are combine with membrane protein and form a
'micropore‘ and increase the cell permeability (ions, amino acids
and other water soluble substances move out through hydrophilic
side forms) allowing leakage of a variety of small molecules
• Cholesterol, present in host cell membranes, closely resembles
ergosterol; the polyenes bind to it as well, though with lesser
affinity.
6. Antifungal Drugs- Polyene antibiotics
• Mechanism
of
action
of
amphotericin, imidazoles, triazoles, and allylamines in fungi.
7. Antifungal Drugs- Polyene antibiotics
• Antifungal spectrum/ Activity:
Active against a wide range of yeasts and fungi
It is fungicidal at high and static at low concentrations
Amphotericin B has clinical activity against Candida spp., Cryptococcus
neoformans, Blastomyces dermatitidis, Histoplasma capsulatum,
Sporothrix schenckii, Coccidioides immitis, Paracoccidioides
braziliensis, Aspergillus spp., Penicillium marneffei, and the agents of
mucormycosis.
Amphotericin B active on various species of Leishmania. Amphotericin
B has limited activity against the protozoa Leishmania braziliensis and
Naegleria fowleri. The drug has no antibacterial activity.
Amphotericin B resistant noted in Candida (Candida lusitaniae) in a
selected group of leucopenic cancer patients. Aspergillus terreus may
be more resistant to amphotericin B than other Aspergillus species
8. Antifungal Drugs- Polyene antibiotics
Pharmacokinetics
• Amphotericin B is not absorbed orally. For intestinal candidiasis it
can be given orally (oral formulation, cannot be used for systemic
fungal infection).
• The intravenous suspension (with deoxycholate), distributed in
body and has more than 90% bound by serum proteins properties.
• The drug is widely distributed in most tissues
• Only 2-3% of the blood level is reached in cerebrospinal fluid; poor
CSF penetration, thus occasionally necessitating intrathecal
therapy for certain types of fungal meningitis.
9. Antifungal Drugs- Polyene antibiotics
Pharmacokinetics
• The serum t1/2 is approximately 15 days. Hepatic impairment,
renal impairment, and dialysis have little impact on drug
concentrations, and therefore no dose adjustment is required.
• About 60% of the drug (amphotericin B) metabolized in liver and
is excreted slowly in the bile and urine over a period of several
days.
10. Antifungal Drugs- Polyene antibiotics
Therapeutic Uses:
• Broad spectrum of activity and fungicidal action
• Used as the initial induction regimen for serious fungal infections
and is then replaced by one of the newer azole drugs for chronic
therapy or prevention of relapse (important for immunosuppressed
patients and those with severe fungal pneumonia, cryptococcal
meningitis).
• For treatment of systemic fungal disease, amphotericin B is given by
slow intravenous infusion at a dosage of 0.5-1 mg/kg/d
• Mycotic corneal ulcers and keratitis can be cured with topical drops
as well as by direct subconjunctival injection
• Amphotericin B given once weekly has been used to prevent
relapse in patients with AIDS who have been treated successfully
for cryptococcosis or histoplasmosis.
• Amphotericin B is most effective drug for resistant cases of kala
azar and mucocutaneous leishmaniasis
11. Antifungal Drugs- Polyene antibiotics
Adverse Effects
• Acute reaction:
– Acute reaction: Chills, fever, aches, pain all over, nausea, vomiting and
dyspnea lasting for 2-5 hours (due to release of cytokines IL, TNF-α)
– Intensity of reaction decreases with continued medication
– Injection of hydrocortisone 0.6 mg/kg with the infusion may reduce the
intensity of reaction.
– Thrombophlebitis of the injection vein can occur.
• Long-term reaction:
– Nephrotoxicity is the most common (it occurs fairly uniformly and is doserelated)
– manifestations are--azotemia, reduced, g.f.r., acidosis, hypokalemia and
inability to concentrate urine. It reverses slowly and often incompletely after
stopping of therapy.
– Anaemia: Most patients develop slowly progressing anaemia which is due to
bone marrow depression. It is largely reversible.
– CNS toxicity: occurs only on intrathecal injection-headache, vomiting, nerve
palsies, etc.
12. Antifungal Drugs- Polyene antibiotics
• Liposomal amphotericin B
– It has been produced to improve tolerability of i.v. infusion, reduce
toxicity and achieve targeted delivery.
– Special features:
• produce mild acute reaction on i.v. infusion
• can be used in patients not tolerating infusion of conventional AMB
formulation
• lower nephrotoxicity
• minimal anemia
• deliver AMB to reticuloendothelial cells in liver and spleen
– Specially indicated for empirical therapy in febrile neutropenic
patients not responding to antibacterial antibiotics.
– Dose: 10 mg, 25 mg per vial inj.; 10 mg/2 ml, 50 mg/10 ml and
100 mg/20 ml inj.
13. Antifungal Drugs- Polyene antibiotics
• Nystatin
– it is a tetraene macrolide produced by Streptomyces noursei
– Nystatin is structurally similar to amphotericin B and has the same mechanism
of action.
– Nystatin is not absorbed from the gastrointestinal tract, skin, or vagina.
– It is too toxic for parenteral administration and is only used topically. Nystatin
is active against most candida species and is most commonly used for
suppression of local candidal infections. Some common indications include
oropharyngeal thrush, vaginal candidiasis, and intertriginous candidal
infections.
– Infections of the nails and hyperkeratinized or crusted skin lesions do not
respond.
– Powders are preferred for moist lesions and are applied two or three times a
day. Creams or ointments are used twice daily. Allergic reactions to nystatin
are very uncommon.
– Used for monilial diarrhoea; monilial vaginitis; corneal, conjunctival and
cutaneous candidiasis
14. Antifungal Drugs- Polyene antibiotics
• Hamycin
– it was isolated from S. pimprina
– similar to nystatin, but more water soluble.
– use is restricted to topical application for oral thrush, cutaneous
candidiasis, monilial and trichomonas vaginitis and otomycosis by Aspergillus.
15. Antifungal Drugs- Echinocandins
• Caspofungin
– It is first and prototype of the Echinocandins
– It is water soluble, lipopeptide antifungal drug derived form
fermentation product of Glarea lozoyensis
– It is active against Candida and Aspergillus
– Inhibiting the enzyme β-1, 3-glucan synthase (unique component of
the fungal cell wall) and thereby disturbing the integrity of the fungal
cell wall. Cross linking between chitin (a fibrillar polysaccharide) and β1, 3-glucan gives toughness to the fungal cell wall. Weakening of the
cell wall by caspofungin leads to osmatic susceptibility of fungal
cell, which then succumbs.
16. Antifungal Drugs- Echinocandins
• Caspofungin
– Pharmacokinetics:
• Caspofungin not absorbed orally; has to be given intravenously.
• Well distributed in tissues, not in CSF.
• Caspofungin is primarily metabolized by the liver (metabolic transformationhydrolysis and N-acetylation)
• Excreted in urine as well as faeces with a plasma t1/2 of 10 hrs
• About 97% of serum drug is bound to albumin
– Approved for deep and invasive candidiasis, esophageal candidiasis
and salvage therapy of nonresponsive invasive aspergillosis
– ADR:
acute
febrile
reaction
can
occur
some
rash, vomiting, dyspnoea, hypokalemia and join pain may occur.
– Available dose: 70 mg in 10 ml/ 50 mg in 10 ml inj.
times;
17. Antifungal Drugs- Heterocyclic Benzofuran
GRISEOFULVIN
– Griseofulvin is a very insoluble fungistatic drug derived from a species of
Penicillium griseofulvum. Its only use is in the systemic treatment of
dermatophytosis.
– Griseofulvin is active against most dermatophytes, including Epidermophyton,
Trichophyton, Microsporum, etc., but not against Candida and other fungi causing
deep mycosis.
•
Mechanism of Action:
– Bind to microtubules and prevents spindle formation and mitosis in fungi. In
mammalian cells, high concentrations of griseofulvin causes disruption of the
mitotic spindle by interacting with polymerized microtubules. Although the effects
of the drug are thus similar to those of colchicine and the vinca alkaloids, its
binding sites on the microtubular protein are distinct.
18. Antifungal Drugs- Heterocyclic Benzofuran
GRISEOFULVIN
•
Pharmacokinetics:
– The absorption of griseofulvin from g.i.t. is somewhat irregular because of its very
low water solubility. Absorption is improved by taking it with fats and by
microfining the drug particles; now ultramicrofine particle preparations from
which absorption is still better are available.
– Griseofulvin gets deposited in keratin forming cells of skin, hair and nails
– Griseofulvin is largely metabolized in liver (methylation), and excreted in urine.
– Plasma t1/2 is 24 hr, but it persists for week in skin and keratin.
•
ADR: Toxicity is low and not serious. Headache, GIT disturbance, CNS symptoms and
peripheral neuritis
19. Antifungal Drugs- Heterocyclic Benzofuran
GRISEOFULVIN
•
Use:
– Mycotic disease of the skin, hair, and nails due to Microsporum, Trichophyton, or
Epidermophyton responds to griseofulvin therapy.
– Griseofulvin is used orally only for dermatophytosis.
– It is a fungistatic and not fungicidal
– Duration treatment is depends upon site of infection
– Ineffective topically
– Dose: 125-250 mg QID with meals
• Scalp: 4 weeks
• Palm soles: 6- 8 weeks
• Finger nails: 6-8 months
• Toe nails: 10-12 months
– Griseofulvin is given for cases with nail, hair or large body surface
involvement. It is effective in athletes foot, but not in pityriasis versicolor.
20. Antifungal Drugs- Heterocyclic Benzofuran
GRISEOFULVIN
•
Interactions:
– Induces CYP450 enzyme and hastens warfarin metabolism
– Effect of oral contraceptives may be lost
– Reduce the phenobarbitone oral absorption
