Download 5-Antifungal Chemotherapy

Reading assignments:
Katzung’s Basic & Clinical Pharmacology,
13th Edi ,Ch-48,p825-834;
Dr.Sanjib Das
• III. Antifungal Chemotherapy
– Understand why selective toxicity against
fungal pathogens is more difficult to achieve
than is antibacterial selectivity
– Know the mechanisms of action,
pharmacokinetics, and clinical uses of the
antifungal drugs
– Know the adverse effects of antifungal drugs
•
•
•
•
•
A. Antifungal azoles
B. Membrane-active agents
C. Antimetabolites
D. Griseofulvin
E. Terbinafine
Overview of Fungal Infections
Fungal infections can be broadly divided into three
groups:
Systemic Mycoses
Subcutaneous Mycoses
Superficial Mycoses
Systemic Mycoses
-Most common causative organisms belong to the genera Aspergillus,
Blastomyces, Candida, Coccidioides, Cryptococcus, and
Histoplasma.
-Type of infection
Soft Tissue Infection,
UTI,
Pneumonia,
Meningitis, or
Septicemia (Fungemia).
Systemic Mycosis Occurs both in immunocompetent and
immunocompromised individualsBlastomycosis
Coccidioidomycosis and
Histoplasmosis
Systemic fungal infection that occurs ONLY in immunocompromised
or debilitated personsAspergillosis
Candidiasis
Cryptococcosis, and
Mucormycosis
Subcutaneous Mycoses
are often caused by puncture
wounds contaminated with soil
fungi.
Chromomycosis,(Warty
nodules that progress to
"cauliflower-like" appearance
at site of inoculation )
Pseudallescheriasis(Myceto
ma, Draining sinus tracts at
site of inoculation )
Sporotrichosis.(Nodules and
ulcers along lymphatics at site of
inoculation)
Superficial Mycoses:
-Infections of the nails, skin and mucous
membrane
-Restricted to epidermis (dead layer) as those
organisms live on keratin
Caused by either
-DERMATOPHYTES OR YEASTS
Dermatophyte causing infections are
-Epidermophyton
-Microsporum, and
-Trichophyton.
-These infections usually present as a rash with
pruritus and erythema.
-Some dermatophytes are called Ringworm
and infection caused by them is annular,
scaling rash w/ a clear center.
-Dermatophyte infections of the nails (Tinea
unguium or Onychomycosis)
Tinea pedis (athlete’ foot), Tinea capitis
(ringworm of the scalp), Tinea corporis
(ringworm of the body), and Tinea cruris (“jock
itch”).
Yeasts causing infections
are
-Candida albicans
-other Candida species.
Patients may present with
Thrush (oral candidiasis) ,
Vaginal candidiasis, or
Candida infections of the
axilla, groin, and gluteal
folds (including diaper
rash).
Candida granuloma & chilosis
Polyene Antibiotics
-Amphotericin B
-Natamycin
-Nystatin
Azole Derivatives
Allylamine Drugs
Echinocandin
-Clotrimazole
-Econazole
-Fluconazole
-Itraconazole
-Ketoconazole
-Miconazole
-Naftifine
-Terbinafine
-Anidulafungin
-Caspofungin (prototype)
-Micafungin
Other Antifungal Drugs
-Ciclopirox
-Flucytosine
-Griseofulvin
-Tolnaftate
Anti-Fungal Chemotherapy
• Fungi are eukaryotes
• Very difficult to
achieve selective
toxicity
• Commonly occur in
debilitated or
immunosuppressed
patients
Terbinafine
Ketoconazole
Fluconazole
Itraconazole
Voriconazole
Nystatin
Amphoterecin B
Liposoamal Ampt B
Caspofungin
An intravenous drug that inhibits the synthesis of glucan, a major fungal cell wall component.
Use: invasive aspergillosis in patients who failed amphotericin B therapy
Mechanism of Antifungal Drugs
Exploring Mech. of Resistance from Mech. of Actions
• A gene coding an enzyme that synthesizes a particular
fungal cell wall polysaccharide is mutated. A fungal
pathogen might, in this way, develop resistance to
which of the following agents?
• A fungal pathogen has been found accumulating low
ergosterol in the cell membrane. Which drug probably
would not work against this pathogen (due to
development of resistance) if to be prescribed ?
• A fungal pathogen has been found activating a type of
ATP binding cassettes on the cell membrane & thus
enhances efflux of an an antifungal drug. Which drug
is it?
Figure out each group of drugs as fungostatic/fungocidal
by logically exploring Mech. of Actions…..not always true
as dose, type of organism also determine the aforesaid
properties
Amphotericin B--Polyene antibiotic
-Binds to ergosterol in fungal
membranes & forms artificial “ pores”
-Resistant strain have low ergosterol
Pharmacokinetics--Must give IV or intrathecal
-Very slow excretion, t ½ about 2
weeks (biphasic half life, with an
initial half life of about 24 hours and a
terminal half life of 15 days.)
Preparations
Amphotericin B is available in two parenteral formulations for systemic
and subcutaneous infections:
-a deoxycholate complex (conventional) and
-a new Amphotericin B Lipid Complex (also called
Liposomal Amphotericin B-- "reservoir" of amphotericin)
– Liposome has lower affinity for drug than does fungal membrane
(ergosterol),Higher affinity for drug than does patient membrane
(cholesterol)
[Drug in Fungal Membrane]
[conc]
10
[Drug in Liposome] [Drug in Human Membrane]
1
0.1
Amphotericin B lipid complex protects kidneys and other organs
from the drug’s toxicity while preserving its antifungal activity.
An analogy
Amphotericin B: Clinical Aspects
Clinical Uses
• Logically DOC or Co-DOC in most of the Severe Systemic Mycoses such
as Aspergillus (high dose), Candida, Cryptococcus, Histoplasma, Mucor,
Sporothrix.
• Often (but not always) combined with Flucytosine
– Delay resistance
– Use lower doses due to synergism
Adverse effects
Magic bullet for numerous bad
fungi but amphoterrible for host
Infusion related-(immediate)
• Usually see chills, fever, nausea, vomiting, headache (Usually due to
Histamine release)
• Alleviated partly by pretreatment with NSAIDs,H1 antihistaminics
Adverse effects----contd…..
Dose dependant
• Nephrotoxicity (as ATN) includes ↓GFR, tubular acidosis,↓K+ & Mg++
& anemia through ↓erythropoietin . Nephrotoxicity common, often
irreversible (Reduced with liposomal preparation)
• Numerous other common adverse effects
Mixed infection
or Empirical
therapy-N+N=NO
Pt. receiving a systemic antifungal drug developed
puffiness or face, oliguria, swelling of hands & feet
,dizziness , palpitation and tremor. An ECG reveals
tall T wave ,ST segment depression & frequent
premature ventricular beats. Lab. Investigation
suggests Hgb of 5.5 mg/dl & serum potassium level
of below 1.5mEq/L. Pull out the key information from
this vignette to diagnose this clinical condition.
Which drug possibly can cause this? Coadministration of which diuretic would result into
reduced efficacy of it’s own?
Flucytosine
Mechanism
• Activated by fungal cytosine deaminase—converted to 5-fluorouracil
which after triphosphorylation (FUTP) is incorporated into fungal RNA
(↓RNA synthesis)
5FU also forms 5-Flurodeoxyuridine monophosphate (5 –Fd-UMP) which
inhibits Thymidylate synthase→↓Thymine (↓DNA synthesis)
Pharmacokinetics
• Orally effective, widely distributed, including CNS
•
Excreted in urine-- urine levels 10x serum levels
Adverse Effects
• Low toxicity to patient (not activated in mammalian cells)
Clinical Use
• Narrow spectrum
•
Resistance develops rapidly, use only with amphotericin B
Anti-Fungal Azoles
Mechanism
Inhibit ergosterol synthesis (fungal CYPs) by inhibiting
14 α demethylase ,a fungal CYP450 enzyme ,which converts
Lanosterol to Ergosterol (1. cross inhibition of host CYP450 2.decreased host
cholesterol synthesis with some of these drugs)
Resistance occurs due to decreased intracellular accumulation of azoles
(other antimicrobials using pump?)
Imidazoles include Ketoconazole (topical & systemic), Miconazole (topical),
Econazole (topical) and Clotrimazole (topical).
The Triazoles include Itraconazole (Both topical & systemic) , Fluconazole
(Both topical & systemic) & Voriconazole (Both topical & systemic).
One Imidazole (Ketoconazole,a bad choice although) & all Triazoles
(Itraconazole, Fluconazole and Voriconazole) are used to treat
systemic infections.
Ketoconazole—
-1st effective oral antifungal for systemic disease
-Absorbed and distributed, except to CNS
Itraconazole- Broader spectrum but does not cross BBB, fewer adverse effects than
ketoconazole
-DOC in Blastomycoses,Sporotrichoses
Voriconazole– effective against a variety of fungal infections, including
invasive Aspergillosis, fluconazole-susceptible and -resistant Candida
infections, and Cryptococcus neoformans
Fluconazole–
-Water-soluble azole
-DOC or Co-DOC in most systemic fungal infection (less toxic than
AMB)
-Good CSF delivery (prophylaxis & supression of cryptococcal
meningitis)
-more selective for fungal P450s
Clotrimazole & MiconazoleUsed topically
• Pharmacokinetics
-effective orally
-absorption of Ketoconazole is ↓ by antacids (as azoles slightly acidic)
-absorption of Itraconazole is ↑ by food(as acidity increases with food)
-only fluconazole penetrates into CSF and can be used in meningeal
infection.
-ketoconazole & Itraconazole are metabolized by liver enzymes
-inhibition of hepatic CYP450s
S/E
-↓Steroid synthesis including cortisol & testosterone-Altered metabolism &
Antiandrogenic effects respectively (cross inhibition of host 14 alfa
demethylase responsible for host steriod synthesis)
-elevated LFT & rare hepatotoxicity
Echinocandin Antifungal Drugs
•
Examples
– Anidulafungin
– Caspofungin (prototype)
– Micafungin
•
Mechanism of action
– Inhibits the synthesis of β(1,3)-D-glucan, which is an essential component of the
fungal cell wall
•
Uses
– Treatment of invasive Aspergillus infections in patients who are refractory or
intolerant of other therapy
– Treatment of candidemia and other Candida infections
(1) Intra-abdominal abscesses
(2) Esophageal and peritonitis in pleural space
(3) Empirical treatment for presumed fungal infections in febrile neutropenic
patients
•
Adverse effects
–
–
–
–
–
Hypotension and tachycardia
Fever, chills and headache
Rash
Anemias
Hypokalemia
Anti-Fungal Agents for Mucocutaneous Infections
Topical antifungal agents—
•
Nystatin-- Similar to amphotericin B, too toxic for systemic use.Swish &
swallow in oral candidiasis,topical for diaper rash or vaginal candidiasis.
Systemic Drugs for Topical Infection-Griseofulvin
– Active only against Dermatophytes (Administered orally), concentrates
in newly formed keratinized tissue .
– Act by disrupting microtubular structure
– Delivery for treatment of ringworm athlete's foot
– Disrupts the mitotic spindle in fungal cells
A/E :
-Potent CYP450 Inducer
-Disulfiram like effect
Terbinafine
– Similar pharmacokinetics to griseofulvin, but also can be used topically
– Inhibits squalene epoxidase (ergosterol synthesis)
A/E :
-Possible Hepatotoxicity
Chemotherapeutic agents
Antibacterial agents
Antifungal agents
Antiparasitic agents
Antitumor agents
Antiviral agents
Amphotericin B
Liposomal Ampho-B
Flucytosine
Antimalarials
Ketoconazole
Fluconazole
Itraconazole
Chloroquine
Mefloquine
Primaquine
Anthelmintic drugs
GABA Ivermectin strongyloidiasis
 tremetodes &
Ca Praziquantel
cestodes
Tub Thiabendazole
Tub Mebendazole
Ach Pyrantel pamoate
Griseofulvin
Terbinafine
Antiprotozoal drugs
Metronidazole
TrimethoprimSulfamethoxazole
PyrimethamineSulfadoxine
Pentamidine
PCP
A 55-year-old construction worker had
a mild respiratory infection with flu-like
symptoms that resolved in less than 2
weeks. Two months later, a chest
radiograph revealed numerous diffuse
calcific densities confirming a diagnosis of
primary histoplasmosis. Which of the
following binds to ergosterol and would be
appropriate for treating this patient?
A.
B.
C.
D.
E.
Amphotericin B
Flucytosine
Itraconazole
Nystatin
Terbinafine
Answer: A
Amphotericin B & nystatin
bind to ergosterol;
toxicity due to binding to
cholesterol in host cells
PowerPoint Slides
 Several of the PowerPoint slides are Copyright © 2002-04,
the American Society for Pharmacology and Experimental
Therapeutics (ASPET). All rights reserved.
 Some of slides in this session are from the above mentioned format
and are free for use by members of ASPET.
 Some others are from various sources like text book, recommended
books, slides of Dr. S. Akbar (ex. professor, Pharmacology ,MUA).
 Core concepts of various USMLE High yield review series like
Kaplan ,BRS etc. are thoroughly explored & integrated whenever
necessary