11. Mechanism of action
Amphotericin B
Binds ergosterol in fungal cell membrane
Form pores in cell membrane
Cell contents leak out
Cell death
12. Antifungal spectrum
- Aspergillus
- Blastomyces dermatitidis
Broadest spectrum
- Candida albicans of action
- Cryptococcus neoformans
- Coccidioides immitis Fungicidal at high &
static at low conc.
- Histoplasma capsulatum
- Mucor spp.
Also active against Leshmania
13. Mechanism of resistance
• Resistance:
– Replacement of ergosterol by other sterols in
fungal plasma membrane.
– Resistance is not a problem clinically.
14. Pharmacokinetics
• Poorly absorbed orally
• Insoluble in water so colloidal
suspension prepared with sodium
deoxycholate(1:1 complex)
• 90% bound to plasma proteins
• Metabolized in liver slowly
excreted in urine
• t ½ = 15 days
15. Administration & dose
• Systemic mycosis: IV
– Available as 50mg vial – suspended in 10 ml water
and then diluted with 500 ml glucose
– 0.5mg/kg to 1 mg/kg
– Total dose- 3-4 gm over 2-3 months
• Intestinal Monoliasis: 50-100 mg QID Orally
• Vaginitis: topical
• Otomycosis: 3 % drops
• Intrathecal: 0.5 mg BD in fungal meningitis
16. Uses
• Useful drug in nearly all life threatening mycotic
infections
• Treatment of invasive aspergillosis
• Rapidly progressive Blastomycosis &
Coccidiomycosis
• Cryptococcus neoformans
• Mucormycosis.
• Disseminated rapidly progressing Histoplasmosis
• Reserve drugs for resistant kala azar
• Topical uses:
17. • Adverse events:
– Acute reaction:
– Chills, fever, headache, pain all over,
nausea, vomiting, dyspnoea lasting 2-5 hrs
because of release of IL & TNF
– can be treated with hydrocortisone
0.6mg/kg
– Long term toxicity:
– Nephrotoxicity: Azotemia,
Hypokalemia, acidosis, ↓ GFR
– anemia
– CNS toxicity : intrathecal administration,
headache, vomiting, nerve palsies
– Hepatotoxicity rarely
18. Disadvantages of AMB
SIDE AmphotericinAMB toxic
EFFECTS OF B is
Nephrotoxicity
Acute infusion related reactions
Hypopotassemia, anemia, hepatic
dysfunction..
19. Lıpıd formulations of amphotericin B
Amphotericin B Lipid Complex
(ABLC; Abelcet®)
Amphotericin B Colloidal Dispersion
(ABCD; Amphocil® or Amphotec®)
Liposomal Amphotericin B
(L-AMB; Ambisome®)
20. ABLC
AMB Lipid complex (ABLC):
35% AMB incorporated in
ribbon like particles of
dimyristoyl phospholipids
Ribbon-like particles
Carrier lipids: DMPC, DMPG
J Liposome Res 1993; 3:
451
21. ABCD
AMB colloidal
dispersion (ABCD):
Disc shaped
particles
containing 50%
each of AMB &
cholesteryl ester in
Disk-shaped
aqueos dispersion particles
Carrier lipid: Cholesteryl sulfate
J Pharmaceutics 1991; 75:
45
22. The ‘LIPOSOME’..
•Liposomal AMB (Small
unilamellar vesicles) :
10% AMB
incorporated in
SUV made up of
lecithin
Lipid formulations:
20-50 times more
expensive than
AmB-deoxycholate
Hospital Practice 1992; 30: 53
23. Major advantages of lipid AMB
formulations
Macrophage
Milder acute reaction
Liposome Lysosome
Can be used in intolerance
Fusion
to conventional preparations Liposome
degradation
Lower nephrotoxicity & Endocytosis
anemia
Deliver AMB to RES of liver Endocytic
vesicle
speen so useful in leshmania
Release in blood Release from
& immunocompromised compartment macrophage
Can be used in higher doses Liposomes in the therapy of infectious
diseases and cancer 1989: 105
24. Nystatin
Obtained from S.Noursei
Similar to AMB in antifungal properties, high
systemic toxicity so used locally only
Poorly absorbed from mucus membrane
Available as ointment ,cream , powder, tablet
Uses:
5 lac U in intestinal moniliasis TDS
1 lac U in vaginitis
Prevention of oral candidiasis
Can be used in oral, cutaneous, conjunctival candidiasis
Adverse events:
Gastointestinal disturbances with oral tablets
25. Hamycin:
S. Pimprina
Hindustan antibiotics pimpri
More water soluble, fraction absorbed orally but
unreliable in systemic infections
Topical use in thrush, cutaneous candidiasis,
trichomonas & monilial vaginitis, otomycosis by
aspergillus
Natamycin:
Similar to nystatin, broad spectrum
Used topically 1%, 3% ointment
Fusarium solani keratitis, trichomonas & monilial
vaginitis
26. Griseofulvin
• One of early antibiotics from penicillium
griseofulvum
• Fungistatic, systemic drug for superficial
fungal infections
• Active against most dermatophytes
• Dermatophytes concentrate it actively hence
selective toxicity
• Resistance: loss of concentrating ability
27. • Mechanism of action:
– Griseofulvin interacts with
polymerized microtubules and
disrupts the mitotic spindles thus
arresting fungal mitosis
• Pharmacokinetics:
– Oral administration, irregular
absorption, increased by fatty food
and microfine particles
– Gets conc in keratinized tissue
– Metabolized in liver, excreted in
urine,t1/2=24 hrs
30. • Uses:
– Systemically only for dermatophytosis, ineffective
topically
• Systemic azoles more effective and preferred
• Duration of treatment depends on site,
thickness of keratin and turnover of keratin.
• Treatment must be continued till infected
tissue is completely replaced by normal
skin,hair, nail.
• Dose: 125-250 mg QID
31. Duration of treatment
• Body skin = 3 weeks
• Palm, soles = 4- 6 weeks
• Finger nails = 4- 6months
• Toe nails = 8 – 12 months
• Griseofulvin should be reserved for nail hair or
larger body surface involvement
• Interactions:
– Warfarin , OCP
– Phenobarbitone, Disulfiram like reaction
32. 5 flucytosine
– Prodrug, pyrimidine analog, antimetabolite
– Converted to 5 FU
– Human cells cant convert it to 5FU
– Adverse events:
• Bone marrow toxicity , GIT , Alopecia, skin rashes,
itching , rarely hepatitis
– Uses: in combination with AMB in cryptococcal
meningitis
– Narrow spectrum of action
33.
34. Advantages of combination:
–Entry of 5 FC
–Reduced toxicity
–Rapid culture conversion
–Reduced duration of therapy
–Decreased resistance
35. • Differences between AMB & 5 FC
• AMB = Active drug, broad spectrum, antibiotic,
fungicidal
• Not absorbed, high protein binding, no BBB,
metabolized in liver, highly efficacious,
IV,Intrathecal,topical
36. • Azoles:
– Synthetic antifungals
– Broad spectrum
– Fungistatic or fungicidal depending on conc of
drug
– Most commonly used
– Classified as imidazoles & triazoles
• Imidazoles: Two nitrogen in structure
– Topical: econazole, miconazole, clotrimazole
– Systemic : ketoconazole
– Newer : butaconazole, oxiconazole, sulconazole
37. • Triazoles : Three nitrogen in structure
– Fluconazole, itraconazole, voriconazole
– Terconazole: Topical for superficial infections
• Both these groups are
– Structurally related compounds
– Have same mechanism of action
– Have similar antifungal spectrum
39. Miconazole & clotrimazole
• Topical use:
– Miconazole 2 % and clotrimazole 1 % applied BD for
2 weeks in pityriasis versicolor, 4 weeks in cruris,
capitis and corporis
• Uses:
– Dermatophyte infections
– Candida: oral pharyngeal, vaginal, cutaneous
• Adverse events:
– Local irritation , itching or burning
– Miconazole shows higher incidence of vaginal irritation &
pelvic cramps
40. Ketoconazole
– First orally effective broad spectrum antifungal
– Effective against
• Dermatophytosis, Deep mycosis , Candidiasis
41. Pharmacokinetics
• Effective orally
• acidic environment
favours absorption
• High protein binding
• Readily distributed, not to
BBB
• Metabolized in liver,
excreted in bile
• t1/2 = 8- 10 hrs
• Dose : 200 mg OD or BD
44. Uses
• Dermatophytosis: conc in stratum corneum
• Monilial vaginitis : 5-7 days
• Systemic mycosis: blastomycosis,
histoplasmosis, coccidiodomycosis
– Less efficacy than AMB & slower response
– ↓Efficacy in immunocompromized and meningitis
– Lower toxicity than AMB higher than triazoles
• High dose used in cushings syndrome
• Topical: T.pedis, cruris, corporis, versicolor
45. Fluconazole
• Newer water soluble triazole
– Oral, IV as well as topical
– Broad spectrum antifungal activity
• Candida, cryptococcosis, coccidiodomycosis
• Dermatophytosis
• Blastomycosis
• Histoplasmosis
• Sporotrichosis
• Not effective against aspergillosis & mucormycosis
46. Pharmacokinetics
94% oral bioavailability
Not affected by food or gastric pH
Primarily excreted unchanged in urine t1/2 =
25 -30 hrs
Poor protein binding
Widely distributed crosses BBB
47. Adverse events
GIT upset
Headache, alopecia, skin rashes, hepatic necrosis
Teratogenic effect
CYP450 Enzyme inhibiting property less Interactions:
Effects hepatic drug metabolism to lesser extent than
Ketoconazole
H2 blockers & PPI do not effect its absorption
No anti androgenic & other endocrine effects
48. Uses
Candida:
150 mg oral dose can cure vaginal candidiasis with
few relapse
Oral candidiasis- 2 weeks treatment required
Tinea infections & cutaneous candidiasis: 150 mg
weekly for 4 weeks, tinea unguim : 12 months
systemic fungal infections: Disseminated
candidiasis, cryptococcal, coccidiodal meningitis
200-400 mg / day 4- 12 weeks or longer
Meningitis: preferred drug
Eye drops for fungal keratitis
49. Itraconazole
Broadest spectrum of activity also against
aspergillus
Fungistatic but effective in
immunocompromised
Does not inhibit steroid hormone synthesis
and no serious hepatoxicity
50. Pharmacokinetics
50-60% bioavailability, absorption is variable,
enhanced by food & gastric acidity
High protein binding 99 %
Well distributed accumulates in vaginal
mucosa, skin, nails but CNS penetration is poor
Metabolized in liver CYP3A4 excreted in feces
t1/2= 30- 64hr
51. Uses
DOC for paracoccidomycosis & chromoblastomycosis
DOC for histoplasmosis & blastomycosis
Esophageal, oropharyngeal vaginal candidiasis
Not superior to fluconazole : 200 mg OD X 3 days
Dermatophytosis: less effective than fluconazole
100- 200 mg OD X 15 days
Onychomycosis : 200 mg / day for 3 months
Intermittent pulse regime 200 BD once a week / month for 3
months equally effective
Aspergillosis: 200 mg OD/ BD with meals for 3 months
or more
52. Adverse events
• GI Intolerance
• Dizziness, pruritis , headache , hypokalemia
• Increase plasma transaminase
• Rarely hepatotoxicity
• Drug interactions:
– Oral absorption ↓by antacids, H2 blockers
– Rifampicin, phenytoin induce metabolism
– Inhibits CYP3A4 drug interaction profile similar to
ketoconazole
53. Triazoles
Itraconazole Fluconazole
- Varied absorption. - Completely absorbed and
Metabolized by cyt P450 better tolerated, Renal
excretion
- less endocrine effects but - Less endocrine effects
occur at high doses
- Penetrates well into CSF
- Less penetration in CSF
- Many drug interactions - Drug Interactions
(due to inhibition of CYT
P450/ 3A4)
54. Voriconazole
II generation triazole
High oral bioavailability, low protein binding
Good CSF penetration
Metabolized by CYP2C19
Doesn’t require gastric acidity for absorption
T1/2= 6 hrs
Uses:
DOC for invasive aspergillosis
Most useful for esophageal candidiasis
First line for moulds like fusarium
Useful in resistant candida infections
55. Dose and Adverse effects
• Dose : 200 mg BD
• Adverse events:
– Transient visual changes like blurred vision ,
altered color perception & photophobia
– Rashes in 5 -6 %
– Elevated hepatic enzymes
– Prolongation of QT
56. Terbinafine
Orally & topically effective drug against
candida & dermatophytes
Fungicidal : shorter courses of therapy
required & low relapse rates
Mechanism of action:
Pharmacokinetics:
Well absorbed orally 75%
Highly keratophilic & lipophilic
High protein bound , poor BBB permeability
t1/2- 15 days
Negligible effect on CYP450
57. Adverse events and uses
Adverse events:
Nausea , vomiting , Diarrhoea
Taste disturbances
Rarely hepatic dysfunction
Topical: erythema , itching , dryness , urticaria,
rashes
Uses:
Dermatophytosis: topically/ orally 2- 6 weeks
Onychomycosis: first line drug 3- 12 months
Candidiasis: less effective 2- 4 weeks therapy may
be used as alternative 250 mg OD
58. Caspofungin acetate
Semisynthetic antifungal
MOA: Inhibits B (1,3) D glucan an essential
component of fungal cell wall
Uses: Treatment of invasive aspergillosis &
candidiasis (esophageal, intraperitoneal)
Dose: IV 70 mg slowly then 50 mg daily infusion
Adverse events:
Flushing rashes , nausea, vomiting, phlebitis
59. Topical agents used in dermatophytosis
Tolnaftate:
Tinea, cruris, corporis, 1- 3 weeks treatment
Not effective in hyperkeratinized lesions
Salicylic acid aids its effect by keratolysis
Ciclopirox olamine:
Tinea infections, pitryasis versicolor ,dermal
candidiasis, vaginal candidiasis
Penetrates superficial layers
Acts by inhibiting membrane uptake of precursors
of macromolecules needed for fungal growth
60. Topical agents used in dermatophytosis
• Undecyclenic acid: 5% (Tineafax)
– Generally combined with zinc (20%)
– Requires prolonged treatment has high relapse
rate
– Weaker antifungal action used in tinea cruris and
nappy rash
• Sodium thiosulfate: (Karpin lotion)
– Reducing agent known as hypo
– Effective in pitryasis versicolor only 20 % solution
for 3-4 weeks
61. Topical agents used in dermatophytosis
• Benzoic acid:
– Used in combination with salicylic acid
– Whitfields ointment: ( benzoic acid 6% + salicyclic
acid 3 %)
– Salicyclic acid due to its keratolytic action helps to
remove infected tissue & promotes penetration of
benzoic acid in fungal infected lesion
– Adverse events: irritation & burning sensation
(Ring cutter ointment)
64. Spectrum of action
AMB 5FC KTZ FLU ITR
Aspergillus -- -- -- Y
Blastomycosis -- Y Y Y
cryptococcus Y -- Y Y
Coccidiodo -- Y Y Y
candida Y Y Y Y
Histoplasma -- Y Y Y
mucor -- -- -- --
Sporotrichosis -- -- Y Y
chromoblast dermatophyte Fusarium
65. Spectrum of action
• Nystatin: Candidiasis only
• Griseofulvin: Dermatophytosis only
• Terbinafine : Dermatophytosis & candidiasis
• Caspofungin: Aspergillosis & candidiasis
66. Important characteristics
• Broad spectrum: AMB, KTZ, FLU, ITR
• Resistance: 5 FC
• Nephrotoxic/ Anemia: AMB
• Leucopenia: 5 FC
• GIT upset: All
• Over all toxicity: highest for AMB lowest for
fluconazole, itraconazole
Notas do Editor
Name polyene is derived from highly double bonded structure
amphotericin B combines avidly with lipids (ergosterol) along the double bond-rich side of its structure and associates with water molecules along the hydroxyl-rich side. This amphipathic characteristic facilitates pore formation by multiple amphotericin molecules, with the lipophilic portions around the outside of the pore and the hydrophilic regions lining the inside. The pore allows the leakage of intracellular ions and macromolecules, eventually leading to cell death. Some binding to human membrane sterols does occur, probably accounting for the drug's prominent toxicity.
Dermatophytes are inhibited in vitro but conc of AMB attained inskin are low and ineffective
Bile salt –doc60% metabolized in liver, excretion occurs slowly in both urine and bile
Started at 0.3 mg/kg – 0.7 mg/kg , 1 mg test dose injected over 20 min to see acute reaction
Owing to its broad spectrum of activity and fungicidal action, amphotericin B remains a useful agent for nearly all life-threatening mycotic infections, although newer less toxic agents have largely replaced amphotericin B for most conditions. It is often used as the initial induction regimen in order to rapidly reduce fungal burden and is then replaced by one of the newer azole drugs (described below) for chronic therapy or prevention of relapse. Such induction therapy is especially important for immunosuppressed patients and those with severe fungal pneumonia, severe cryptococcal meningitis, or disseminated infections with one of the endemic mycoses such as histoplasmosis or coccidioidomycosis. Once a clinical response has been elicited, these patients then often continue maintenance therapy with an azole; therapy may be lifelong in patients at high risk for disease relapse. For treatment of systemic fungal disease, amphotericin B is given by slow intravenous infusion at a dosage of 0.5–1 mg/kg/d. It is usually continued to a defined total dose (eg, 1–2 g), rather than a defined time span, as used with other antimicrobial drugs.
ameliorated by slowing the infusion rate or decreasing the daily dose. Premedication with antipyretics, antihistamines, meperidine, or corticosteroids can be helpful. When starting therapy, many clinicians administer a test dose of 1 mg intravenously to gauge the severity of the reaction. This can serve as a guide to an initial dosing regimen and premedication strategy.
Used in superficialcandidiasis,
Torula, chromoblastomyces, candida some strains
Available as Cream, gel, spray, lotion, pessary ,. ( pedis, cruris, corporis, versicolor)
Most toxic among azoles so not used so much triazolespreferedAcidic environment favours absorption so orange juice increases absorption and proton pump inhibitors decrease absorption. But saturation of metabolism occurs shortly which prolongs the its half life and permits once daily dosing , since small amount of drug appears in urine it is not suitable for
Not used in fungal meningitis
Much less toxic than AMB but more side effects than fluconazole, itraconazoleNausea etc can be minimized by taking with food
Proton pump inhibitors : decrease absorption Rifampicin, phenytoin increase metabolism With sulfonylureas can cause hypoglycemia Nephrotoxicity can occur with cyclosporine H2 receptor blockers ↑ Srconc of cisapride, terfenadine, astemizole, quinidinePhenytoin toxicity Sulfonylureas: hypoglycemiaCyclosporine: nephrotoxicityWarfarin: bleeding Rifampicin, phenytoin ↑ metabolism of ketoconazoleShould not combine with AMB
200 mg OD Also tried in dermal leshmaniasis
Oral candidiasis : fluconazole 200 mg on first day then 100 mg daily for atleast 2 weeksCryptococcosis: 400 mg daily 8 weeks after stabilization with amb , after 8 weeks dose is reduced to 200 mg for life aids related only Coccodiodal meningitis: drug of choice Fluconazole has activity against histoplasma, blasto, sporotrich , ring worm but efficacy less Nor against aspergillusAll azoles not against mucormycosis. Children doses = 3-6 mg/kg
Capsule form of drug better absorbed in fed state , invasive aspergillosis outside the CNSIN treating deep mycosis two 100 mg capsules given twice daily with food , divided doses increase the AUC WHY PULSE THERAPY: retention of active drug in nail keratin . Daily therapy prefered for recurring infection. Terbinbafine 250 mg OD better in onychomycosis than itraconazole
effective against candida & aspergillosis
Not effective in hyperkeratinized lesions like tineapedis , tineacapitis , tineaunginum as poor penetration , symptomatic relief occurs early with tolnaftate but if discontinued before fungal bearing tissue is shed relapses occur