3. Introduction
• These drugs used for superficial and deep fungal infections.
• Systemic mycoses, such as histoplasmosis, coccidioidomycosis,
cryptococcosis, blastomycosis, paracoccidioidomycosis, and
sporotrichosis, are caused by primary or “pathogenic” fungi that can
cause disease in both healthy and immunocompromised individuals.
• In contrast, mycoses caused by opportunistic fungi such as Candida
albicans, Aspergillus, Trichosporon, Torulopsis (Candida) glabrata,
Fusarium, Alternaria, and Mucor are generally found only in the
immunocompromised host.
4. Classification
A. Antibiotics: Polyenes (amphotericin B, nystatin, hamycin,
natamycin), Heterocyclic benzofuran (Griseofulvin)
B. Antimetabolites : flucytosine
C. Azoles : imidazole (topical- clotrimazole, econazole, miconazole,
systemic- ketoconazole), Triazole (systemic- fluconazole,
itraconazole)
D. Allylamine : terbinafine
E. Other topical agents : tolnaftate, undecylenic acid, benzoic acid,
Quiniodochlor, ciclopirox olamine, sodium thiosulphate
5. Polyene antibiotics
• The name derived from highly double bonded structure.
• Amphotericin B is described as prototype.
• Drugs
• Amphotericin B: obtained from Streptomyces nodosus
• Nystatin: obtained from Streptomyces noursei
• Hamycin: obtained from Streptomyces pimprina
• Natamycin (primaricin) : same like hamycin s. pimprina
6. Amphotericin B
Hydrophilic OH
groups
Macrocyclic ring
Lipophilic conjugated
double bonds
Polar amino-
sugar and
carboxylic acid
group
This all three group are insoluble in water and
unstable in aqueous medium.
7. • Mechanism of AMB:
• Polyenes have higher affinity for ergosterol present in the fungal cell
membrane.
• They get into the membrane with the help of ergosterol and make a
micropore by combination of several molecules.
• The hydrophilic side forms the interior of pore through which ions,
amino acids and other water soluble substance moved out.
8.
9. • Anti-fungal spectrum:
• It is active against the wide range of yeast and fungi: candida albicans,
Histoplasma capsuatum, cyprococus neoformans, Blastomyces
dermatitidis, Coccidioides immitis, Torulopsis, etc.
• Dermatophytes are inhibited in vitro, but concentrations of AMB
attained in infected skin are low and ineffective.
• It is fungicidal at high and static at low concentration.
10. • Pharmacokinetic
• It is not absorbed, can be given orally for intestinal candidiasis without
systemic toxicity.
• Administered i.v. as a suspension made with deoxycholate, it gets widely
distributed in the body, but with that poor penetration in CSF.
• It binds to sterols in the tissue and to lipoproteins in plasma and stay in the
body for long period.
• Terminal elimination half-life is 15days.
• 50% is metabolised in liver.
• Excretion occurs slowly both in urine and bile, here urinary concentration
of active drug is low.
11. • Administration and dose:
• For intestinal moniliasis: oral- 50 to 100 mg QID
• For systemic mycosis: suspend powder with 10 ml water than dilute it
with 500 ml of glucose, give 1 mg test dose i.v. , after 20 mins if
reaction not occur than 0.3 mg/kg infused for 4-8 hrs. daily dose
gradually increased to 0.7 mg/kg depending on tolerance of patient.
Total dose 3-4 gm given for 2-3 months.
• For fungal meningitis: intrathecal injection of 0.5 mg twice weekly
• For vaginitis, otomycosis: topical 50 to 100 mg
13. • Adverse effects : the toxicity of AMB is high
• Acute reaction: occurs when each infusion consist of chills, fever,
aches and pain all over, nausea, vomiting and dyspnoea lasting 2-5hr
probably due to release of cytokines.
• It going to be severe when dose gradually increased.
• Injection of hydrocortisone 0.6 mg/kg with the infusion may reduce
the intensity of reaction.
• Thrombophlebitis (inflammatory process cause blood clot and the
vein) occur in the injected vein.
14. Long term toxicity:
• Nephrotoxicity is most important: occurs at fairly uniform dose.
Manifestations are: azotaemia, reduced GFR, acidosis and inability to
concentrate urine.
It reverse slowly and often incompletely after stoppage of therapy.
• Anaemia: most patient develop slowly progress anaemia because of
bone marrow depression. It is reversible.
• CNS toxicity: occurs only through intrathecal injection- headache,
vomiting, nerve palsies (lack of function),etc.
15. • Uses:
• Topically for oral, vaginal and cutaneous candidiasis and octomycosis.
• Most effective drug for various systemic mycoses
• Gold standard for antifungal therapy
• Leishmaniasis: it is reserve drug for resistant cases of kala azar and
mucocutaneous leishmaniasis.
16. Nystatin
• Similar to AMB in antifungal action and other properties.
• nystatin having higher toxicity so it is used generally locally in
superficial candidiasis.
• Given orally used for monilial diarrhoea 5 lac U TDS(1 mg=2000U)
have bad taste in mouth are only side effect.
• Combined with tetracycline and given in superinfection diarrhoea.
• Effective in monilial vaginitis- 1 lac U tab inserted twice daily.
• For oral thrush: vaginal tab has been crushed and mixed with
glycerine for application in mouth.
• For corneal, conjunctival and cutaneous candidiasis: ointment
17. Hamycin
• Similar to nystatin, but more water soluble.
• A fraction orally administered dose is absorbed but cant relied upon
for the treatment of systemic mycosis.
• Can be used in topical application for oral thrush, cutaneous
candidiasis, monilial and trichomonas vaginitis and octomycosis by
Aspergillus.
• For topical : 5 lac U/g ointment, 2 lac U/ml suspension
• For vaginal ovules: 4 lac U
18. Natamycin (pimaricin)
• Similar to nystatin, has a brooder spectrum of action, used topically.
• 5% suspension or 1% ointment is non-irritating to the eye and has
been used particularly in Fusarium keratitis.
• For vaginal infection: 2% cream, 25 mg tablet and 100 mg tab
19. Heterocyclic Benzofuran
• One of early antibiotic excreted from penicillium griseofulvum.
• Active against most dermatophytes like, Epidermophyton,
Trichophyton, Microsporum,etc.
• But not against candida and other fungi causing deep mycosis.
20. Griseofulvin
• Mechanism of action:
• It interferes with mitosis- multinucleated and stunted fungal hyphae
result from its action.
• It also causes abnormal metaphase configuration.
• It binds to polymerised microtubules and somehow disorients them.
21.
22. • Pharmacokinetic
• Irregular absorption from GIT because it have low water solubility.
• Absorption increased by taking it with fats and by micro fining the
drug molecule.
• It deposits in keratin forming cells of skin, hair and nails.
• Thus duration of treatment is dependent upon the site of infection,
thickness of infected keratin and its turnover rate.
• largely metabolised by methylation and excreted in urine.
• Half-life is 24 hrs, but it persist for weeks in skin and keratin.
23. • Adverse effect:
• Low and not serious
• Headache is common complain followed by GI disturbances.
• Rashes and photo allergy may warrant discontinuation.
• Transient leukopenia and albuminuria are infrequent.
24. • Uses:
• Orally for dermophytes
• Effective in athletes foot infection
• Tinea infections
25. • Interactions:
• Reduce warfarin metabolism
• Reduce efficacy of oral contraceptives
• Phenobarbital reduce absorption and metabolism of griseofulvin
• Cause intolerance to alcohol
26. Antimetabolites
• Flucytosine
• Pyrimidine antimetabolites which is inactive as it is.
• Its taken up by fungal and converted into 5-Flurouracil and then to 5-
flurodeoxyuridylic acid which is inhibitor of thymidylate synthesis
which is component of DNA.
• Narrow spectrum
27. • Adverse effect:
• Dose-dependent bone marrow depression
• GI disturbances
• Diarrhoea
• Enteritis
• Liver dysfunction is mild and reversible.
28. • Uses:
• Not employed as the sole therapy except occasionally in
chromoblastomycosis.
• Rapid resistance development limits its utility in deep mycosis.
29.
30. Imidazole and triazoles
• Most extensively used anti-fungal drugs
• Broad spectrum antifungal activity : dermatophytes, candida, fungi
involved in deep mycosis, nocardia, some gram positive and
anaerobic bacteria.
• The mechanism of action of imidazole and triazoles is the same.
31. • Mechanism of action:
• They inhibit fungal cytochrome P450 enzyme “lanosterol 14-
demethylase” and thus impair ergosterol synthesis.
• This process leads to cascade of membrane abnormalities in the
fungus.
32. Clotrimazole
• Effective in topical treatment
• Tinea infection like ringworm: 60-100% cure in 2-4 weeks, apply two
times a day
• Also used in athletes foot infection, otomycosis,
oral/cutaneous/vaginal candidiasis.
• Also effective in skin infection caused by corynebacteria.
• Well tolerated by most patients
• Local irritation with stinging and burning sensation occurs in some
• No systemic toxicity seen after topical use.
33. Econazole
• It is similar to clotrimazole.
• Same way penetrates in skin layers and is highly effective in
dermatophytosis, otomycosis, oral thrush.
• Inferior to clotrimazole in vaginitis
• No adverse effects, except local irritation in few
34. Miconazole
• It is highly efficacious drug for tinea, pityriasis versicolor, otomycosis,
cutaneous and vulvovaginal candidiasis.
• Because it have good penetrating power, is has been found effective,
single application on skin acts for few days.
• Irritation after cutaneous application is infrequent.
• No systemic adverse effect
35. Ketoconazole
• First orally effective broad-spectrum antifungal drug, used in both
dermatophytes and deep mycosis.
• The oral absorption of ketoconazole is facilitated by gastric acid
because its more soluble in low pH.
• Hepatic metabolism is extensive and metabolites excreted in urine
and faces.
• Half life is dose dependent and varies in 1 and half hr to 6 hrs.
• Penetration in CSF is less so not effective in meningitis.
• Usual dose is 200 mg OD or BD
36. • Adverse effects:
• Less toxic than AMB
• Most common side effects are nausea and vomiting
• Followed by loss of appetite, headache, rashes and hair loss.
• Gynaecomastia (increase in size of breast tissue in male), loss of hair
and libido, oligozoospermia(low concentration of sperm in semen)
• Menstrual irregularities
• Contraindicated in pregnant and lactating women
37. • Interactions:
• H2 blockers, proton pump inhibitor and antacids decrease absorption
• Rifampicin, carbamazepine, phenobarbitone, phenytoin induce its
metabolism and reduce its efficacy.
• Ketoconazole raises blood levels of following: phenytoin, diazepam,
digoxin, haloperidol, warfarin, sulfonylureas, statins, cyclosporine,
nifedipine, HIV protease inhibitors.
• Dangerous interaction with terfenadine, astemizole and cisapride
resulting in polymorphic ventricular tachycardia. Due to this
withdrawal of these drugs from market in many country.
38. • Uses:
• Orally for dermatophytes
• Orally in monilial vaginitis for 5-7 days
• Orally for systemic mycosis
• Occasionally in dermal leishmaniasis and kala azar
• High dose is used in Cushing's syndrome.
