Antifungal Drugs
Lorna G. Amoranto, RMT, RN, MD, DPPS
Antifungal Drugs
Fungal infectious occur due to :
1- Abuse of broad spectrum antibiotics
2- Decrease in the patient immunity
Types of fungal infections
1. Superficial : Affect skin – mucous membrane
Tinea versicolor
Dermatophytes : Fungi that affect keratin layer of skin,
hair, nail
tinea pedis
ring worm infection
Candidiasis : Yeast-like
oral thrush
vulvo-vaginitis
nail infections
2- Deep infections
Affect internal organs
lung – pneumonia
heart – endocarditis
brain - meningitis
Classification of Antifungal Drugs
1- Antifungal Antibiotics :
Griseofulvin
Polyene macrolide : Amphotericin- B & Nystatin
2- Synthetic :
Azoles :
Imidazoles : Ketoconazole , Miconazole
Triazoles : Fluconazole , Itraconazole
Flucytosine
Squalene epoxidase inhibitors
Terbinafine & Naftifine
Classification According to Route of
Administration
Systemic :
Griseofulvin , Amphotericin- B , Ketoconazole ,
Fluconazole , Terbinafine
Topical
In candidiasis :
Imidazoles : Ketoconazole , Miconazole.
Triazoles : Terconazole
Polyene macrolides : Nystatin , Amphotericin-B
Gentian violet : Has antifungal & antibacterial
Amphotericin B
Produced by Streptomyces nodosus.
Amphoteric polyene macrolide
Pharmacological Effect: broad-spectrum
Mechanism: binds to ergosterol in fungi
(cholesterol in humans and bacteria) to form
pores
Pharmacokinetics:
Poorly absorbed from the
gastrointestinal tract
More than 90% bound by serum
proteins
Metabolized in liver, excreted slowly in
the urine
Adverse Effects:
Infusion-Related Toxicity: fever, chills,
muscle spasms, vomiting, headache,
hypotension
Slower Toxicity:
Renal toxicity
K+↓, Mg2+↓
Anemia: erythropoietin ↓
Abnormalities of liver function
Neurologic sequelae
Liposomal Amphotericin B
Lipid preparations reduce
toxicity without sacrificing
efficacy
Lipid formulations
distributes mostly in
reticular endothelial tissue
(liver, spleen, lung), but less
in kidney
Griseofulvin
 Derived from a species of penicillium
Fungistatic drug
Insoluble
Administered in a microcrystalline form only
using in the systemic treatment of
dermatophytosis
Deposited in newly forming skin where it binds
to keratin, protecting the skin from new infection
Azoles
Synthetic compounds
Classification: according to the number of
nitrogen atoms in the five-membered azole ring
Imidazoles: Ketoconazole, Miconazole, Econazole,
Clotrimazole, Bifonazole
Triazoles: Itraconazole, Fluconazol, Vorionazole →
systemic treatment
Mechanism of Action
Reduction of ergosterol synthesis by inhibition of
fungal cytochrome P450 enzymes
Greater affinity for fungal than for human cytochrome
P450 enzymes
Imidazoles exhibit a lesser degree of specificity than
the triazoles, accounting for their higher incidence of
drug interactions and side effects
Ketoconazole
 first oral azole introduced into clinical use
 Less selective for fungal P450
 Inhibition of human P450 interferes with
biosynthesis of adrenal and gonadal steroid
hormones
 Alter the metabolism of other drugs
 Best absorbed at a low gastric pH
Miconazole, Econazole, Clotrimazole
Bioavailability is low by taking
orally
 Used topically
Itraconazole
Its absorption is increased by food and by low
gastric pH
Treatment of dermatophytoses and
onychomycosis
The only agent with significant activity against
aspergillus species
Fluconazole
Water soluble and good cerebrospinal fluid
penetration
The widest therapeutic index of the azoles
Treatment and secondary prophylaxis of
cryptococcal meningitis
Voriconazole
A broad spectrum antifungal agent
Given orally or IV
High oral bioavailability
Penetrates tissues well including CSF
Inhibit P450
Used for the treatment of invasive aspergillosis & serious
infections.
Reversible visual disturbances
Acrylamide
Include Naftifine and Terbinafine
non-competitive and reversible inhibitor of Squalene
epoxidase
Terbinafine is synthetic, oral formulation
Fungicidal
Treatment of dermatophytoses, especially
onychomycosis, more effective than griseofulvin or
itraconazole
Antituberculosis
Drugs
Therapeutic Goals:
(1) Prevention or prophylaxis
(2) Cure of clinical disease
(3) Requirements:
a) Prolonged therapy
b)Combined therapy
c) Compliance
d) Prevention of development of drug resistance
e) Cures, ideally, 95-100%
Properties of Mycobacterium tuberculosis:
a) Cell wall -- high lipid (60% dry weight) content
b) Mycolic acid a major component
c) Slow growth
d) Survive within phagocytes
Isoniazid (INH)
General comments:
(1) Prophylaxis as single agent
(2) Cure -- ALWAYS in combination
Slows development of resistance
Isoniazid (INH)
Antibacterial activity:
 Bacteriostatic at most concentrations (is bactericidal to actively growing organisms)
Mechanism of action:
 Inhibits mycolic acid synthesis.
 Resistance:
 1998 - 8-10% of isolates in US are resistant (10-20% in Caribbean and Southeast
Asia). Organisms may be Multidrug-resistant.
Adverse Effects:
Allergic, Including fever, skin eruptions, hepatitis, and
various kinds of rashes
Hematological reactions, e.g., thrombocytopenia,
agranulocytosis, eosinophilia, and anemia may occur
Reversible vasculitis may occur and arthritic symptoms at
various joints may be observed.
Adverse Effects
Most frequent -- Hepatitis
2 types
a)minor increase in liver
aminotransferases
No need to stop drug, 10-20%
of cases
asymptomatic
b) Clinical hepatitis in 1%
can be fatal
Stop drug
Adverse Effects
 Most notable -- peripheral neuritis (including optic neuritis)
 in 10-20% if given > 5 mg/kg/d
 infrequent in standard dose of 300 mg/adult (Assuming 70 kg as
standard, 300 is 4.3 mg/kg)
 Predisposing conditions
slow acetylators
Malnutrition
Alcoholism
Diabetes
AIDS
Uremia
 Supplement with pyridoxine (Vitamin B6)
Rifampin
Mechanism of Action:
Binds to DNA-dependent RNA polymerase
Inhibits initiation -- not elongation
Antibacterial Spectrum:
M. tuberculosis
Bactericidal
Broad spectrum of bacteria
Many Gram– bacteria
Chlamydia
Pharmacokinetics
Oral
Well absorbed
Broadly distributed -- even CSF
Orange-red color stains tissues / secretions / urine
Enterohepatic cycling and partially biotransformed in liver
Drug and metabolites eliminated in feces
Autoinduction of metabolism
Half-life shortens 40% first 14 days of Rx
Hepatic microsomal induction
Clinical uses
(1) Tuberculosis, Never used alone for Therapy of TB
(2) Leprosy
(3) Various bacterial infections, e.g., with a beta-lactam or
vancomycin for staphylococcal endocarditis.
Meningococcal and staphylococcal carrier states
Adverse reactions
Relatively safe, less than 4% in TB patients have
significant reactions
Drug interaction
Hepatic microsomal induction
Shortens half-life of many drugs
Resistance
Frequency of resistance is 1:106 organisms (M.
tuberculosis)
Develops quickly, due to changes in the beta
subunit of DNA-dependent RNA polymerase
Not use drug alone for TB or other bacteria
Ethambutol
Activity:
No effect on bacteria other than mycobacteria
Suppresses growth (static) of organisms resistant to
streptomycin and isoniazid, i.e., no cross resistance
Resistance to ethambutol develops
Mechanism
Not clear
May interfereRNA synthesis
inhibits synthesis of component of mycobacterial cell
wall – arabinogalactan
may increase penetration of other drugs into the
organisms
Clinical use
Always used in combination.
Adverse reactions
Minimally toxic (<2%) at 15 mg/kg per day (usual dose)
 decreased visual acuity, rash, drug fever.
Optic neuritis (reversible) -- most important adverse effect
and dose related
Occurs in 15% of patients receiving 50 mg/kg per day and
5% of those receiving 25 mg/kg per day and <1% 15
mg/day
Decreased visual acuity and red/green color blindness
Pyrazinamide
Activity
Bactericidal to tubercle bacilli within monocytes
at 12.5 μg/ml
requires slightly acidic pH
Resistance develops rapidly when used alone.
Mechanism: unknown
Pharmacokinetics:
Orally administered at 1 gram gives 45 μg/ml at 2
h and 10 μg/ml at 15 h
Normal dose is 20-30 mg/kg po)
Broadly distributed
Eliminated primarily by glomerular filtration;
also biotransformed
Adverse reactions
most common and serious side effect is liver
injury.
Other anti-tuberculosis dugs:
Streptomycin
Rifapentine
Rifandin
Para-aminosalicylic acid
Ethionamide
Amikacin
Fluoroquinolones