ANTIMICROBIAL DRUGS III

(ANTI-FUNGAL)
Med 7610: GENERAL CONCEPTS AND
PRINCIPLES OF DISEASE AND
THERAPEUTICS

ELEUS J. FAJARDO, M.D., MHA

 AT THE END OF THE SESSION, THE
STUDENT MUST:

1.  Be able to differentiate a fungal from other

forms of infections.
2.  Know the treatment for the different fungal
infections
3.  Be able to apply the proper medication for a
specific fungal infection.
 CONTENTS:
§  FUNGAL VS. BACTERIAL/VIRAL INFECTIONS
§  CHARACTERISTICS OF FUNGAL INFECTIONS
§  DRUGS USED IN THE TREATMENT OF
FUNGAL INFECTIONS
§  MECHANISM OF ACTION OF THE DIFFERENT
DRUGS
§  SIDE-EFFECTS
§  ASSESSMENT
 THE FOLLOWING ARE INFECTIONS OF
THE SKIN. IDENTIFY WHETHER:
A.  It is a viral infection
B.  It is a bacterial infection
C.  It is a fungal infection

1 2 3
 GENERAL FEATURES OF FUNGAL INFECTIONS

Fungus can cause infections in human beings because

they are present in the air or in the soil.

The characteristic features of the infection are as

follows:
1.  It may begin in the lungs or on the skin
2.  They are rarely serious unless the patients are
immuno-compromised or have been taking
medications for a long period of time.
5.  They usually progress very slowly
6.  Drugs can be taken either orally, topically or
through the IM/IV route.
CLASSIFICATION OF FUNGAL INFECTIONS:
1.  Opportunistic
2.  Primary

OR
1.  Local
2.  Systemic
OPPORTUNISTIC FUNGAL INFECTIONS OCCUR IN
IMMUNOCOMPROMISED HOST

PRIMARY FUNGAL INFECTIONS OCCUR IN THOSE

WITH COMPETENT IMMUNE SYSTEM
OPPORTUNISTIC FUNGAL INFECTION:
1.  Candidiasis
2.  Aspergillosis
3.  Mucormycosis

PRIMARY FUNGAL INFECTION:

1.  Usually occurs when an individual inhales spores
2.  Usually produces localized pneumonia as its
primary symptomatology
3.  They are geographically located, i.e.
Coccidiodomycosis is found mostly in northern
Mexico, Washington, Central and South America
 DRUGS USED IN THE TREATMENT OF FUNGAL
INFECTIONS*

Alter cell
membrane Block Beta Block nucleic Disrupts
permeability glucan synthesis acid synthesis microtubule
function

Echinocandins Flucytosine
Griseofulvin
Azoles Polyenes Terbenafines
DRUGS FOR SYSTEMIC FUNGAL INFECTIONS
1.  Drugs that alter cell membrane permeability:
A. Polyene derivative:
a.1. Amphothericin B
MOA * contains hydrophilic and lipophilic molecules
* binds to ergosterol, a sterol which is specific
to fungal cell membranes
* by binding to ergosterol it creates artiicial
pores

Pharmacokinetics:
* poorly absorbed in the GIT
* given intravenously
* widely distributed to all tissues except the
CNS
 Pharmacokinetics:
* half life is 2 weeks
* excreted mainly in the liver but some maybe
found in the urine
* widely distributed to all tissues except the
CNS
* it is not dialyzable

Clinical Uses:
* one of the most important drug for treatment
of systemic mycoses
* it is used initially to start treatment before
shifting therapy to azoles
Clinical Uses:
* one of the most important drug for treatment of
systemic mycoses
* it is used initially to start treatment before
shifting therapy to azoles
* it has the widest antifungal spectrum
* it is the drug of choice for a lot of fungi, i.e.
histoplasma, blastomyces, candida
albicans among others
* it is given by slow IV
* maybe given intrathecally if patient is
suffering from meningitis
Toxicity:
* Related to:
1. Infusion rate
2. Dose limitation
3. Neurotoxicity

Infusion related: * If given by rapid infusion, may cause

fevers, chills, vomiting and a fall in blood
pressure
* It is highly recommended that infusion
should be given slowly
Dose limitation: * It decreases glomerular filtration rate
causing renal tubular acidosis with
concomitant loss of potassium and
magnesium
Toxicity:
* Related to:
1. Infusion rate
2. Dose limitation
3. Neurotoxicity

Infusion related: * If given by rapid infusion, may cause

fevers, chills, vomiting and a fall in blood
pressure
* It is highly recommended that infusion
should be given slowly
Dose limitation: * It decreases glomerular filtration rate
causing renal tubular acidosis with
concomitant loss of potassium and
magnesium
Neurotoxicity: * If given intrathecally, may cause cerebral
damage and seizures.
1.  Drugs that alter cell membrane permeability:
B. Azole derivatives:
B.1. Imidazole: Fluconazole
B.2. Triazoles:
Fluconazole Posaconazole
Itraconazole Voriconazole
Isavuconazole
MOA * same as that of Amphothericin B
* In addition, it acts at the 14 alpha
methylation of lanesterol, which is
catalyzed by a fungal p450 isozyme.

Pharmacokinetics:
* except for Ketoconazole, all azoles are well
absorbed in the GI tract
1.  Drugs that alter cell membrane permeability:
Pharmacokinetics:
* except for Ketoconazole, all azoles are well
absorbed in the GI tract
* most are available in tablet and parental
forms
* all of the azoles are widely distributed in all
organ systems
* Fluconazole can penetrate the CSF barrier

Clinical Uses:
1. Ketoconazole:
Ø  Used for chronic mucocutaneous candidiasis
Ø  Effective against dermatophytes
Clinical Uses:
2. Fluconazole:
Ø  Used for infections caused by Coccidiodes
Ø  Drug of choice for candidiasis of the oropharyngeal
and esophageal areas.
Ø  Drug of choice for treatment and secondary
prophylaxis against cryptococcal meningitis
Ø  Its level in the blood is equivalent to that of
Amphotericin B in cases of candida infections

3. Itraconazole:
ü  Drug of choice for treatment of Blastomyces and
Sporothrix
Clinical Uses:
3. Itraconazole:
ü  Drug of choice for treatment of Blastomyces and
Sporothrix
ü  Alternative agent in the treatment of Coccidiodes,
Cryptococcus, Histoplasma

4. Voriconazole:
o  Has a wider spectrum of activity than Itraconazole
o  It is used as a codrug in the management of invasive
Aspergillosis

5. Posaconazole:
²  The broadest spectrum antifungal among the
triazoles
Clinical Uses:
5. Posaconazole:
²  Used for prophylaxis against fungal infections in
patients undergoing cancer chemotherapy
² Usually the last drug to be used for invasive
aspergillosis

6. Isavocunazole:
o  It has antifungal spectrum similar to Posaconazole
o  It is better tolerated than Posaconazole

Toxicity:
§  Vomiting, diarrhea
Toxicity:
§  Ketoconazole is an inhibitor of hepatic cytochrome
P450 isoenzymes and may therefore have adverse
drug reactions and increase plasma levels of
cyclosporine, warfarin,oral hypoglycemics, phenytoin

§  Ketoconazole may also produce gynecomastia,

infertility and menstrual irregularities due to its
inhibition of cytochrome P450 isoforms, preventing
the synthesis of gonadal and adrenal steroids

§  Voriconazole has been found to have caused

immediate but transient visual disturbance and
occasional blurring of vision of unknown origin
Toxicity:
§  Voriconazole is classified as Class D drugs in terms of
pregnancy risk in experimental animals.
 ASSESSMENT: Answer the question below by
choosing the right letter:*

A 14-year-old patient has experienced severe headache and

double vision for a month. His temperature is 38.6°C (101.5°F).
His CSF culture was positive for cryptococcal antigen. Which of
the following drugs would be appropriate to treat this patient
systemically (not intrathecally)?
(A)  Amphotericin
(B ) Fluconazole
(C) Itraconazole
(D) Ketoconazole
(E) Nystatin
1.  Drugs that alter cell membrane permeability:
C. Terbinafines
C.1. Terbinafine
C.2. Naftifine
MOA * Inhibits squalene epoxidase, a fungal
enzyme resulting in accumulation of toxic
levels of squalene which results in
preventing ergosterol synthesis.
* It is fungicidal.

Clinical uses and toxicity:

•  Available in oral and topical form
•  It accumulated in keratin
•  Effective in treatment of onychomycosis
•  Gi upset, rash, headache
•  It does not inhibit cytochrome P450
1.  2. Drugs that block beta glucan synthesis
A.Echinocandins
A.1. Caspofungin
A.2. Anidulafungin
A.3. Micafungin
MOA * Inhibits the synthesis of an essential
component of the fungal cell wall, β (1-3)
glucan
* It is fungicidal.

Pharmacokinetics:
§  It is widely distributed in all organ system
§  It is eliminated in the liver
§  Half life of the drugs vary: Caspofungin 9-12 hrs;
Micafundin slightly longer than Caspofungin and
Anidulafungin 24-48 hrs
Clinical Uses:
Ø  Caspofungin
* In patients with disseminated and mucocutaneous
Candida infection resistant to Amphothericin B
* Treatment for mucormycosis

Ø  Anidulafungin
* for invasive and esophageal candidiasis

Ø  Micafungin
* for mucocutaneous candidiasis
* as prophylaxis against candida infection in bone
marrow transplant patients.
Toxicity:
§  Caspofungin when given rapidly through the IV route
produces reactions due to histamine release

§  Micafungin elevates blood levels of

immunosuppressant drugs i.e. cyclosporine and
sirolimus. It also has reations secondary to histamine
release

§  Elevated liver transaminases maybe seen when

cyclosporine and echinocandins are combined
SYSTEMIC DRUGS FOR MUCOCUTANEOUS
FUNGAL INFECTIONS
Drugs used in the treatment of dermatophytoses are
usually given orally. They are the following:
1.  Terbinafine
2.  Azoles
3.  Griseofulvin

GRISEOFULVIN:
MOA: * It inerferes with the microtubule function in
dermatophytes
* Inhibits synthesis and polymerization of
nucleic acids.
Pharmacokinetics:
§  Absorption of the drug is dependent on the physical
state of the drug
§  Ultra micro-sized particles are highly absorbed
§  Absorption of drug is aided by high fat diet
§  It is distributed to the stratum corneum and binds with
keratin
§  Elimination is through the biliary system

Clinical Uses:
§  It is not effective as a topical agent
§  The oral preparation is used for treatment of
dermatophytoses of the skin and hair
Adverse Effects:
v Headache, photosensitivity,GI irritation
v Changes in liver function
v  Should not be given to patients with porphyria
v Decreases bioavailability to warfarin
v Produces disulfam-like effect with intake of ethanol
 TOPICAL ANTI-FUNGAL THERAPY

Topical drugs are usually used for superficial infections

with candida albicans and dermatophytes.
1.  Nystatin:
* Polyene drug
* Used topically to treat candida infection
* Taken orally to eradicate GI fungi in patients with
poor defense mechanism
2. Azole group of drugs
 SUMMARY*

DRUG/DRUG MOA ACTIVITY/ PHARMACOKINE TOXICITIES

CLASS CLINICAL USES TICS/
INTERACTIONS

Amphotericin B Binds to ergosterol in Candidemia and other Multiple forms: IV for Nephrotoxic, infusion
fungal cell infections caused by systemic infections; rate related reactions
membranes, blastomyces, topical for bladder/
cryptocococcus, etc ocular infections
Azoles Inhibit fungal P450- Aspergillosis Various topical and Ketoconazole is
dependent enzymes Blastomycosis oral forms for seldom used in
blocking ergosterol Mucormycosis dermatophytosis systemic infection due
synthesis Alternattive drug for Oral and parenteral to its ability to inhibit
candidemia and other forms for mycoses adrenal and hepatic
infections i.e. Most undergo hepatic P450Voriconazole
histoplasma, metabolism causes blurring of
cryptococcus Fluconazole has vision
excellent CSF Class D risk in
penetration pregnancy

Echinocandins Inhibit β-glucan treatment of IV forms Gastrointestinal

synthase decreasing candidemia Micafungin increases distress
fungal cell wall levels of cyclosporine Flushing from
synthesis and Nifedipine histamine release
 DRUG/DRUG MOA ACTIVITY/ PHARMACOKINETICS/ TOXICITIES
CLASS CLINICAL USES INTERACTIONS
Inhibits DNA and Synergistic with Oral; enters cerebrospinal Bone marrow
Flucytosine
RNA polymerases amphotericin B in fluid suppression
candidemia and Eliminated in the kidneys
cryptococcal infections

Terbinafine Inhibits Mucocutaneous fungal Oral • long duration of action GI upsets,

Naftifine epoxidation of infections • (weeks) headache
squalene • accumulates in keratin
squalene
accumulation is
toxic to fungi
 REFERENCES:

•  Katzung & Trevor’s Pharmacology Examination and Board Reviews,

12th edition pp. 404 – 410

•  Additional references:
•  http://www.msdmanuals.com/home/infections/fungal-infections
•  http://www.mayoclinic.org