2. Spectrum of infection
Superficial – no inflammatory
response
Mucocutaneous – confined to the
superficial layers with inflammation
Subcutaneous –introduced by
trauma, no systemic spread
Deep/systemic – more dangerous.
◦ Usually Opportunistic
IDI Students
10. Antifungal activity of amphotericin B
VERY ACTIVE AVERAGE ACTIVITY
Candida spp
Criptococcus neoformans
Blastomyces dermatitidis
Histoplasma capsulatum
Sporothrix schenckii
Coccidioides immitis
Paracoccidioides
braziliensis
Aspergillus spp
Penicillium marneffei
Candida lusitaniae
Candida tropicalis
Candida parapsilosis
Scedosporium boydii
Fusarium spp
Malassezia furfur
Trichosporon beigelii
IDI Students
11. Mechanism of action of
polyenes
It binds to fungal membrane sterols
(ergosterol) creating artificial pores
.This alters selective permeability
to K+ and Mg2+.
Resistance may develop from
altered sterols or decreased sterols.
IDI Students
13. Clinical uses of amphotericin
B
Systemic fungal infections:
DOC for aspergillosis, mucormycosis,
cryptococcosis, systemic sporotrichosis, and
candidiasis.
Co-DOC with itraconazole or fluconazole for
Histoplasmosis, blastomycosis, and
coccidioidomycosis
Fungal meningitis (IV or intrathecal)
Cryptococcus: IV w/ flucytosine
Coccidioidomycosis: Intrathecally (severe and
difficult to treat)
Cutaneous Candida infection (TOPICAL)
IDI Students
14. Adverse reactions
Parenteral
1) Chills, fever (50%),
2) Renal damage (80%) = DOSE-
DEPENDENT, REVERSIBLE
↓CREATININE Clearance; BUN
MONITER KIDNEY FUNCT. + SALINE
INFUSION (must give lots of fluid to
decrease kidney toxicity)
3) HYPOtension, HYPOkalemia
(supplement K)
4) Anemia caused by ↓ EPO by kidney
IDI Students
16. Polyenes—Amphotericin B
Resistance
◦ Development of resistance in a previously
susceptible species is uncommon
◦ Mechanisms of Resistance
Reductions in ergosterol biosynthesis
Synthesis of alternative sterols that lessen the ability
of amphotericin B to interact with the fungal
membrane
IDI Students
17. Nystatin
similar to amphotericin B
used topically and for GI use
used against candida and
dermatophytes
(Epidermophyton,
Trichophyton, Microsporum).
IDI Students
19. Mechanism of action of
Flucytosine
The selective action of flucytosine is
due to the failure of mammalian cells
to convert flucytosine to its active
metabolites.
IDI Students
20. Mechanism of action of
Flucytosine
Fungal pathogens are capable of deaminating
flucytosine to 5-fluorouracil, a potent antimetabolite
that is used in cancer chemotherapy).
Fluorouracil is metabolized first to 5-fluorouracil-ribose
monophosphate (5-FUMP) by the enzyme uracil
phosphoribosyl transferase (UPRTase, also called
uridine monophosphate pyrophosphorylase).
As in mammalian cells, 5-FUMP then is either
incorporated into RNA (via synthesis of 5-fluorouridine
triphosphate) or metabolized to 5-fluoro-2'-
deoxyuridine-5'-monophosphate (5-FdUMP), a potent
inhibitor of thymidylate synthetase.
DNA synthesis is impaired as the ultimate result of this
latter reaction.
IDI Students
22. Flucytosine
Spectrum of Activity
◦ Active against
Candida species except C. krusei
Cryptococcus neoformans
Aspergillus species
◦ Synergy with amphotericin B has been demonstrated
The altered permeability of the fungal cell membrane produced by
amphotericin allows enhanced uptake of flucytosine
Mechanisms of Resistance
◦ Loss of cytosine permease that permits flucytosine to cross
the fungal cell membrane
◦ Loss of any of the enzymes required to produce the active
forms that interfere with DNA synthesis
Resistance occurs frequently and rapidly when flucytosine is
given as monotherapy
IDI Students
23. Fungal Resistance to
flucytosine
The mechanism for this resistance can
be loss of the permease necessary for
cytosine transport or decreased
activity of either UPRTase or cytosine
deaminase .
IDI Students
24. Clinical uses
Narrow spectrum activity limited to
Candida, cryptococcus and Torulopsis
sp.
Use with other medicines to
↓RESISTENCE and ↑SYNERGISM
with amphotericin B for: cryptococcosis
diseminated or meningeal candidiasis
amphotericin B may ↓ renal excretion of
flucytosine → monitor plasma
[Flucytosine]
w/ intraconazole for:
IDI Students
25. Clinical uses
Flucytosine is used predominantly in
combination with Amphotericin B.
Flucytosine is given orally at 100 mg/kg per
day, in four divided doses at 6-hour intervals.
Dosage must be adjusted for decreased renal
function.
IDI Students
26. 5 - FLUOROCYTOSINE
ADVERSE EFFECTS
• Gastrointestinal intolerance
• bone marrow depression (anemia,
leukopenia, thrombocytopenia)
• Rash
• hepatotoxicity
• Headache
• Confusion, hallucinations, sedation, euphoria
IDI Students
28. Azoles
There are divided into two ;
1. Imidazoles
◦ Miconazole
◦ Clotrimazole
◦ Ketoconazole
2.Triazoles
◦ Itraconazole
◦ Fluconazole
◦ Voriconazole
IDI Students
30. Mechanism of Action of Azoles
inhibit the synthesis of ergosterol by blocking
demethylation (14-demethylase) of lanosterol to
ergosterol - also inhibit cytochrome P450 activity.
IDI Students
31. Triazoles—Spectrum of Activity
Fluconazole Itraconazole Voriconazole Posaconazole
C. albicans +++ ++ +++ +++
C. glabrata + + ++ ++
C. krusei -- + +++ ++
C. tropicalis +++ ++ +++ +++
C. parapsilosis +++ ++ +++ +++
C. lusitanae ++ ++ +++ +++
Aspergillus -- ++ +++ +++
Cryptococcus +++ +++ +++ +++
Coccidioides +++ +++ +++ +++
Blastomyces ++ +++ ++ +++
Histoplasma + +++ ++ +++
Fusarium -- -- ++ ++
Scedosporium -- +/- + +/-
Zygomycetes - - - ++
IDI Students
32. Azole derivatives
• FIRST GENERATION
– Ketoconazole
• SECOND GENERATION
– Fluconazole
– Itraconazole
• THIRD GENERATION
– Voriconazole
– Ravuconazole (BMS-207147)
– Posaconazole
R-120758 SYN-2869 T-8581
VR-9746 VR-9751 (D0870)
IDI Students
33. MOST COMMON INDICATIONS
Tinea Infections (1-4 wks)
Ketoconazole
Terbinafine
Onychomycosis (6wks-1yr)
Itraconazole
Terbinafine
Vaginal Candidiasis (1d-
2wks)
Fluconazole
Nystatin
Oropharyngeal Candidiasis
(7-14d)
o Fluconazole
o Itraconazole
o Nystatin
Esophageal Candidiasis
(14-21d)
o Fluconazole
o Itraconazole
o Voriconazole
Systemic Infections
Fluconazole
Voriconazole
IDI Students
34. Triazoles—Fluconazole
Dose
◦ 100 to 400 mg daily
◦ Renal impairment:
CrCl >50 ml/min, give full dose
CrCl<50 ml/min, give 50% of dose
Dialysis: replace full dose after each session
Drug Interactions
◦ Minor inhibitor of CYP 3A4
◦ Moderate inhibitor of CYP 2C9
Warfarin, phenytoin, cyclosporine, tacrolimus,
rifampin/rifabutin, sulfonylureas
Adverse Drug Reactions
◦ Well tolerated
◦ Nausea
◦ Elevated LFTs
UNC Hospital Formulary
IDI Students
35. Triazoles—Itraconazole
Dose
◦ 200 to 400 mg/day (capsules)
Drug Interactions
◦ Major substrate of CYP 3A4
◦ Strong inhibitor of CYP 3A4
◦ Many Drug Interactions
Adverse Drug Reactions
◦ Contraindicated in patients with CHF due to negative inotropic
effects
◦ QT prolongation, torsades de pointes, ventricular tachycardia,
cardiac arrest in the setting of drug interactions
◦ Hepatotoxicity
◦ Rash
◦ Hypokalemia
◦ Nausea and vomiting
IDI Students
37. Terbinafine
Mechanism of action
Inhibits squalene 2, 3- epoxidase.
Squalene is cidal to sensitive
organisms.
Clinical uses
Used orally for dermatophytes
Adverse effects
include hepatitis and rashes.
Both are rare.
IDI Students
41. Griseofulvin
Mechanism of action
binds to microtubules
comprising the spindles and
inhibits mitosis.
Uses
Tinea infections of the nails and
hair
incorporates into keratin and
protects newly formed skin.
fungistatic
IDI Students
45. The Fungal Cell Wall
mannoproteins
b1,6
glucans
b1,3
chitin
ergosterol
b1,3 glucan
synthase
Cell
membrane
Atlas of fungal Infections, Richard Diamond Ed. 1999
Introduction to Medical Mycology. Merck and Co. 2001 IDI Students
46. Mechanism of action
Inhibits 1,3-b-D-glucan synthase,
which is required for glucan
polymerization in the wall of certain
fungi
IDI Students
48. Echinocandins—Adverse
Effects
Generally well tolerated
Phlebitis, GI side effects, Hypokalemia
Abnormal liver function tests
Caspofungin
◦ Tends to have higher frequency of liver
related laboratory abnormalities
◦ Higher frequency of infusion related pain
and phlebitis
IDI Students
