Transcript (1) Superficial infections

Antifungal Chemotherapy
•
Fungal infections are termed mycoses and can be
divided into:
(1) Superficial infections: affecting skin, nails, scalp or
mucous membranes
(2) Systemic infections: affecting deeper tissues and
organs.
•
Superficial fungal infections can be classified into the
dermatomycoses and candidiasis.
Antifungal Chemotherapy
•
Dermatomycoses are infections of the skin, hair and
nails, caused by dermatophytes. The commonest are
due to Tinea organisms which cause various forms of
“ringworm”.
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In superficial candidiasis, the yeast-like organism
infects the mucous membranes of the mouth (thrush),
the vagina (vaginal thrush).
•
systemic
diseases
(infections) include:
systemic
candidiasis, cryptoccocal meningitis or endocarditis,
pulmonary aspergillosis.
Antifungal Antibiotics
Amphotericine B & Nystatin
• Mechanism of action:
Binds to ergosterol in fungal cell membranes, causing its
damage and increases their permeability
Cell membrane
Yeast cell
cytoplasm
Resistance occurs when ergosterol binding is impaired
Amphotericine B
• Amphotericin B remains the antifungal agent with the
broadest spectrum of action.
• Candida albicans and Cryptococcus neoformans
• Histoplasma capsulatum, Blastomyces dermatitidis, and
Coccidioides immitis
• Aspergillus fumigatus, mucormycosis.
Amphotericine B
• amphotericin B remains a useful agent for nearly all lifethreatening mycotic infections.
• Amphotericin B is often used as the initial induction regimen
to rapidly reduce fungal burden.
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1.
2.
3.
Immunosuppressed patients with :
Severe fungal pneumonia,
severe cryptococcal meningitis,
disseminated histoplasmosis.
Therapeutic use of mphotericinB
Mycotic corneal ulcers and keratitis can be cured with topical
drops as well as by direct subconjunctival injection.
Fungal arthritis has been treated with adjunctive local injection
directly into the joint.
Candiduria responds to bladder irrigation with amphotericin B,
and this route has been shown to produce no significant
systemic toxicity.
Adverse Effects
• Fever, chills, muscle spasms, vomiting, headache, and
hypotension.
Premedication
with
antipyretics,
antihistamines
or
corticosteroids can be helpful.
• Many clinicians administer a test dose of 1 mg intravenously
to gauge the severity of the reaction.
• Main toxicity of Amphotericin is renal. (Azotemia)
80% of patients get reduction in kidney function which
generally recovers after treatment.
Nystatin
• Topical agent
• Creams, ointments, suppositories and others
• oropharyngeal thrush,
• vaginal candidiasis,
• and intertriginous candidal infections.
Antimetabolite Drugs
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Flucytosine is 5-flourocytosine. It is converted to the
antimetabolite 5-FU selectively within the fungus by
the microbial cytosine deaminase.
•
Its subsequently converted to FdUMP which antagonises
thymidylate synthase.
•
DNA synthesis is impaired as the ultimate result of this
latter reaction.
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The selective action of flucytosine is due to the lack or low
levels of cytosine deaminase in mammalian cells, which
prevents metabolism to fluorouracil.
Antimetabolite Drugs
• Flucytosine is absorbed orallyand used predominantly in
combination with amphotericin B or azols. (resistance if used
alone ).
• Clinical use at present is confined to combination therapy,
either with amphotericin B for cryptococcal meningitis or
with itraconazole for chromoblastomycosis.
• It has the usual side effects associated
antimetabolites, ie bone marrow suppression.
with
Azole Antifungal Agents
•
The azole antifungal agents can be divided into two
broad classes : the Imidazoles and the Triazoles.
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They are used topically and systemically. (The systemic
triazoles are metabolized more slowly and have less effect
on human sterol synthesis than do the imidazoles).
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The Imidazoles and Triazoles inhibit fungal sterol 14-ademethylase,
a
microsomal
cytochrome
P450dependent enzyme system.
Azole Antifungal Agents
• In this way, they impair the biosynthesis of the
ergosterol required for the fungal cytoplasmic membrane
which leads to cessation of growth.
The Azole Family
Azole Family
Imidazoles
Triazoles
Ketoconazole
Fluconazole
Miconazole
Itraconazole
Clotrimazole
Voriconazole
Azole resistance has emerged gradually during prolonged azole
therapy, mutations in ERG11, the gene coding for the 14--sterol
demethylase. Cross resistance is conferred to all azoles.
Azoles
1. minor gastrointestinal upset.
2. abnormalities in liver enzymes and, very rarely, clinical
hepatitis.
3. drug interactions because they affect the mammalian
cytochrome P450 system
Systemic Azoles
• Ketoconazole, Itraconozole, Voriconazole and Fluconazole
are used systemically.
• Ketoconazole was the first azole that could be given
orally to treat systemic fungal infections.
• It is well absorbed from the GI tract, distributes widely
but doesn’t enter the CNS.
• Ketoconazole sometimes is used to inhibit excessive
production of glucocorticoids in patients with Cushing's
syndrome.
ketoconazole
• Main hazard with ketoconazole is liver toxicity, which is
rare but can be fatal.
• Other problems include GI disturbances and inhibition of
adrenocortical steroid and testosterone synthesis.
Itraconazole
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Itraconazole (administered orally) has fewer side effects,
more potent, and has a wider spectrum of activity than
ketoconazole.
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Thus, Itraconazole has largely replaced Ketoconazole in the
treatment of most mycoses.
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Itraconazole is the azole of choice for treatment of disease
due to the dimorphic fungi Histoplasma, Blastomyces.
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Itraconazole has activity against Aspergillus sp, but it has
been replaced by voriconazole as the azole of choice for
aspergillosis.
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Itraconazole is used extensively in the treatment of
dermatophytoses and onychomycosis.
OTHER DRUG CONCENTRATION INCREASED
Alfentanil
Alprazolam
Amprenavir
Atorvastatin
Buspirone
Busulfan
Cerivastatin
Cisapride
Cyclophosphamide
Cyclosporine
Delavirdine
Diazepam
Digoxin
Docetaxel
Felodipine
Haloperidol
Indinavir
Loratidine
Lovastatin
Methylprednisolone
Midazolam
Nisoldipine
Phenytoin
Pimozide
Quinidine
Ritonavir
Saquinavir
Sildenafil
Simvastatin
ITRACONAZOLE CONCENTRATION DECREASED
Drugs that decrease gastric acidity
H2-receptor blockers
Proton pump blockers
Simultaneous antacids (includes didanosine buffer)
Carbamazepine
Isoniazid
Nevirapine
Phenobarbital
Phenytoin
Rifampin, rifabutin
St. John's wort
ITRACONAZOLE CONCENTRATION INCREASED
Amprenavir
Grapefruit juice
Indinavir
Lopinavir
Ritonavir
Fluconazole clinical uses
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oropharyngeal candidiasis. Esophageal candidiasis
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Fluconazole has been recommended as continuation
therapy in non-AIDS patients with cryptococcal meningitis
who have responded to an initial course of amphetracine
B and for patients with pulmonary cryptococcosis.
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Fluconazole can be given orally or intravenously. It
reaches high concentrations in the CNS and ocular
fluids and is the agent of choice for most types of
fungal meningitis. (Much less morbidity than with
intrathecal amphotericin B).
Voriconazole
• Voriconazole is the newest triazole. (modified fluconazole)
• Voriconazole a broad spectrum antifungal agent
• Generally used to treat serious, invasive fungal infections.
examples: Invasive aspergillosis, Candidemia
It is available in intravenous and oral formulations.
• Unique side effects associated with voriconazole is transient
visual disturbances.
Echinocandins
• The echinocandins (caspofungin, micafungin,
anidulafungin) are a new class of antifungal agents.
and
• Act as concentration-dependent, noncompetitive inhibitors
of (1,3)-D-glucan synthase, an essential component of the
cell wall of susceptible filamentous fungi that is absent in
mammalian cells.
• Echinocandins are available only as parenteral formulations
• adverse effects of echinocandins include histamine release
resulting in rash, facial swelling, and itchiness.
Caspofungin clinical uses
• currently licensed for disseminated and mucocutaneous
candida infections.
• as well as for empiric antifungal therapy during febrile
neutropenia.
• licensed for use in invasive aspergillosis only as salvage
therapy in patients who have failed to respond to
amphotericin B.
Topical Azoles
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Clotrimazole, Econazole, and
used topically.
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Effective for tinea corporis, tinea pedis, tinea
cruris, tinea versicolor, and cutaneous candidiasis.
They should be applied twice a day for 3 to 6
weeks.
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Miconazole is a potent inhibitor of Warfarin
metabolism and has resulted in bleeding in
Warfarin-treated patient even when Miconazole
applied topically
Miconazole are
Topical Azoles
• Oral clotrimazole troches are available for treatment of oral
thrush and are a pleasant-tasting alternative to nystatin.
• Three vaginal formulations—clotrimazole tablets, miconazole
suppositories, and terconazole cream—come in both low- and
high-dose preparations.
• Adverse local reactions to the imidazoles may include stinging,
pruritus, erythema, and local irritation
Griseofulvin
• It inhibits fungal mitosis by inhibiting mitotic spindle
formation
• Its only use is in the systemic treatment of dermatophytosis.
• it is deposited in newly forming skin where it binds to
keratin, protecting the skin from new infection.
• Adverse Effects -- Headache is the most common side effect.
• Adverse effects include an allergic syndrome much like
serum sickness, hepatitis, and drug interactions with
warfarin and phenobarbital.
Griseofulvin
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2.
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4.
5.
infections of the hair (tinea capitis)
"ringworm" of the skin;
tinea cruris and tinea corporis
tinea of the hands
Griseofulvin also is highly effective in "athlete's foot" or
epidermophytosis involving the skin and nails,
Treatment must be continued until infected tissue is replaced
by normal hair, skin, or nails, which requires 1 month for
scalp and hair ringworm, 6 to 9 months for fingernails, and
at least a year for toenails.
Terbinafine
• A synthetic allylamine that is available in an oral formulation.
• It is used in the treatment of dermatophytoses, especially
onychomycosis.
• Terbinafine is a keratophilic medication, but unlike griseofulvin,
it is fungicidal.
• Like the azole drugs, it interferes with ergosterol biosynthesis,
but inhibits the fungal enzyme squalene epoxidase.
• this leads to the accumulation of the sterol squalene, which is
toxic to the organism.
Terbinafine
• topical uses
1% cream or spray is applied twice daily and is effective in tinea
corporis, tinea cruris, and tinea pedis.