2. Fungal Infection:
Any inflammatory condition caused by a
fungus. Most fungal infections are superficial
and mild, though persistent and difficult to
eradicate. Some, particularly in older,
debilitated, or immunosuppressed or
immunodeficient people, may become systemic
and life threatening. Some kinds of fungal
infections are aspergillosis, blastomycosis,
candidiasis, coccidioidomycosis, and
histoplasmosis.
3. Anti Fungal Agent:
Definition
An antifungal agent is a drug that selectively eliminates fungal
pathogens from a host with minimal toxicity to the host.
Polyene Antifungal Drugs
Amphotericin, nystatin, and pimaricin interact with sterols in the cell
membrane (ergosterol in fungi, cholesterol in humans) to form
channels through which small molecules leak from the inside of the
fungal cell to the outside.
Azole Antifungal Drugs
Fluconazole, itraconazole, and ketoconazole inhibit cytochrome P450-
dependent enzymes (particularly C14-demethylase) involved in the
biosynthesis of ergosterol, which is required for fungal cell
membrane structure and function.
Allylamine and Morpholine Antifungal Drugs
Allylamines (naftifine, terbinafine) inhibit ergosterol biosynthesis at
the level of squalene epoxidase. The morpholine drug, amorolfine,
inhibits the same pathway at a later step.
4. Antimetabolite Antifungal Drugs
5-Fluorocytosine acts as an inhibitor of both
DNA and RNA synthesis via the
intracytoplasmic conversion of 5-fluorocytosine
to 5-fluorouracil.
Therapy:
Therapy literally means curing, healing and is
the attempted remediation of a health problem
usually following a diagnosis. In the medical
field, it is synonymous with the word
"treatment". Among psychologists, the term
may refer specifically to psychotherapy or
"speech therapy".
5. Anti Fungal Therapies:
An antifungal medication is a pharmaceutical
fungicide used to treat and prevent mycoses such as
athlete's foot, ringworm, candidiasis (thrush), serious
systemic infections such as cryptococcal meningitis,
and others. Such drugs are usually obtained by a
doctor's prescription, but a few are available over-the-
counter.
Non-surgical therapies were limited to the use of large
doses of potassium iodide, weak acids such as phenol,
dyes such as methyl violets or other noxious agents
including bromine, potassium permanganate, and oil of
turpentine with olive oil.
6. Antifungals work by exploiting differences between
mammalian and fungal cells to kill the fungal organism
with fewer adverse effects to the host. Unlike bacteria,
both fungi and humans are eukaryotes. Thus, fungal and
human cells are similar at the biological level. This makes
it more difficult to discover drugs that target fungi
without affecting human cells. As a consequence, many
antifungal drugs cause side-effects. Some of these side-
effects can be life-threatening if the drugs are not used
properly.
Antifungal agents (such as ketoconazole) are often found
in antidandruff shampoos. The antifungal drugs inhibit
the yeast Malassezia globosa, which encourages seborrhoeic
dermatitis and tinea versicolor.
7. Prophylactic and preemptive therapy
Empiric therapy
Specific therapy
Clinical trial design for antifungal
compounds
8. The terms prophylaxis, targeted prophylaxis, and preemptive are
often used interchangeably in conjunction with antifungal
therapy. Prophylaxis generally refers to the broad use of
antifungal therapy in a heterogeneous group of patients who are
at variable risk of developing superficial or invasive fungal
infection. By definition, prophylactic antifungal therapy is
administered to patients who are considered to be at risk for
fungal infection, but who have no symptoms of infection at the
time that the antifungal agent is initiated. Prophylaxis may be
systemic (e.g. oral or parenteral fluconazole) or topical (e.g. oral
nystatin). Virtually any population can be given prophylactic
antifungal therapy, but it is typically administered to high-risk
patient populations including selected medical and surgical
intensive care unit (ICU) patients.
9. Preemptive antifungal therapy is administered to
persons who are not only at risk but also have
markers of early infection, for example,
colonization with a fungal pathogen. The group
that has been best described in conjunction with
preemptive therapy is the liver transplant
population who meet criteria for very high risk of
invasive fungal infection including prolonged
intraoperative time, preexisting renal failure, early
colonization with Candida spp., retransplant for
early graft failure, and choledochojejunostomy
anastomosis (Collins et al.1994).
10. Empiric antifungal therapy refers to the use of these
agents among patients with findings and/or symptoms
of suspected invasive fungal disease. The use of empiric
antifungal therapy has been studied most extensively in
persistently febrile and neutropenic patients (Walsh et
al. 1999, 2002; Wingard et al. 2000). The primary goal of
empiric antifungal therapy in this setting is to prevent
breakthrough fungal infections and to treat baseline
infections due to molds and other important fungi in
this uniquely susceptible host. However, all
neutropenic patients are not alike, and the risk of
invasive fungal infection is directly related to the
underlying condition(s) and the duration and depth of
neutropenia.
11. Induction therapy for acute myelogenous leukemia
is associated with a very high rate of invasive fungal
infection and associated high mortality, especially
due to invasive mold infections. Myeloablative
therapy for most solid tumors usually leads to shorter
periods of neutropenia and far less risk of invasive
fungal infection. The appropriate use of empiric
antifungal therapy in the setting of persistent fever
and neutropenia requires that the patient have
persistent fever despite a reasonable course (usually
96 hours or more) of broad-spectrum antibacterial
therapy, and that there is no other obvious
explanation for the clinical deterioration of the
patient. It remains one of the most poorly understood
and understudied areas in the discipline of
antimicrobial therapy.
12. Specific therapy refers to therapy directed at a specific
pathogen which has been detected by culture,
histopathology, and serology, or in the absence of
laboratory evidence, then clinical/radiographic
evidence strongly suggestive of invasive fungal
disease. These include such findings as hepatosplenic
bull’s eye lesions suggesting chronic disseminated
candidiasis, the halo or air crescent sign on chest
suggesting invasive aspergillosis, and disseminated
cutaneous lesions consistent with invasive
candidiasis. Specific therapy is often based on
presumptive evidence of infection, but it is
nonetheless targeted towards the organisms most
likely responsible for the clinical picture.
13. The treatment of central nervous system (CNS)
cryptococcosis has become more uniform because
of data generated fro therapeutic trials among
patients with and without the acquired
immunodeficiency syndrome (AIDS) who have
CNS cryptococcosis (Saag et al. 2000). By contrast,
very few large clinical trials have been done
among patients with less common invasive
mycoses such as aspergillosis,histoplasmosis,
blastomycosis, coccidioidomycosis, and
sporotrichosis. Thus, the ‘gold standard’ of
treatment for these mycoses is often based upon
data generated from smaller comparative studies
without significant power to discern differences in
therapeutic outcome.
14. The design and implementation of the
clinical trials involving antimycotic agents
has been a challenge to clinicians since the
availability of amphotericin B in 1958. The
key challenges to the clinical investigator
include:
Slow patient accrual because of restrictive eligibility criteria for
uncommon diseases
Establishment of meaningful clinical end points
The absence of validated surrogate markers of success or failure (e.g.
serological studies)
The unwillingness of many investigators to perform double-blinded
clinical trials
The need for large numbers of study centers to facilitate completion
of these trials in a reasonable timeframe (Rex et al. 2001).
15. A recently published candidemia treatment trial
enrolled only about 10 percent of all patients with
candidemia at study sites (Pappas et al. 2003; Rex et
al. 2003). Most of these potentially eligible patients
were excluded due to prior antifungal therapy,
abnormal laboratory values, age, comorbid
conditions, and other considerations. Patient accrual
into studies for therapy of invasive aspergillosis has
been even more challenging. In a recent open-label
trial comparing voriconazole to amphotericin B and
other licensed antifungal therapy for the primary
treatment of invasive aspergillosis, it required more
than 5 years and almost 100 centers to enroll almost
300 eligible patients, again reflecting the effect of
restrictive inclusion criteria and the difficulty in
establishing a firm diagnosis of an uncommon
disorder on patient accrual (Herbrecht et al. 2002).
16. Cell membrane
Fungi use principally ergosterol
instead of cholesterol
Cell Wall
Unlike mammalian cells, fungi
have a cell wall
DNA Synthesis
Some compounds may be
selectively activated by fungi,
arresting DNA synthesis.
19. The azoles are a very large group of synthetic agents, which includes
drugs used in bacterial and parasitic as well as fungal infections. The
majority are used as a topical treatment. The drugs listed here are the
few which are suitable for systemic administration. The azoles are
widely used because of their broad therapeutic window, wide spectrum
of activity, and low toxicity.
Members of the azole group have either an imidazole or triazole ring
with N carbon substitution.
Imidazole ring: five-membered ring structure containing two nitrogen
atoms.
Triazole ring: five-membered ring structure containing three nitrogen
atoms.
While ketoconazole was more widely used before the development of
newer, less toxic, and more effective triazole compounds, fluconazole
and itraconazole, its use has now been limited. Unfortunately, azoles
are generally fungistatic (especially in Candida) and resistance to
fluconazole is emerging in several fungal pathogens.
20. The azoles inhibit the fungal P450 enzymes responsible for the synthesis
of ergosterol, the main sterol in the fungal cell membrane. The azoles
act through an unhindered nitrogen, which binds to the iron atom of
the heme, preventing the activation of oxygen which is necessary for
the demethylation of lanosterol. In addition to the unhindered nitrogen,
a second nitrogen in the azoles is thought to interact directly with the
apoprotein of lanosterol demethylase. It is thought that the position of
this second nitrogen in relation to the apoprotein may determine the
specificity of different azole drugs for the enzyme.
The resulting depletion of ergosterol alters the fluidity of the membrane
and this interferes with the action of membrane-associated enzymes.
The overall effect is an inhibition of replication (ie. the azoles are
fungistatic drugs). A further repercussion is the inhibition of
transformation of candidal yeast cells into hyphae-the invasive and
pathogenic form of the parasite.
Since no drug acts with complete specificity, it is not surprising that the
azoles also have some effect on the closely related mammalian p450
enzymes. These are a large family of haem proteins. Hepatic p450
enzymes are involved in the detoxification of drugs whereas
extrahepatic enzymes play an important part in several synthetic
pathways including steroid biosynthesis in the adrenal gland.
22. Treatment:
1. Long-term treatment required
2. Assess response to treatment regularly, as relapses are
common
3. Oral itraconazole 100 mg per day for 6 months is
preferred treatment.
4. Ketoconazole 200–400 mg per day for up to 12 months
almost as effective
5. Oral or parenteral fluconazole 200–400 mg per day for 6
months, if itraconazole or ketoconazole not absorbed
6. Amphotericin B 1.0 mg/kg per day for 4–8 weeks,
followed by sulfadiazine 500–1000 mg at 4 h intervals for
6–12 months; children, 60–100 mg/kg per day in divided
doses
23. Type of disease:
Mild
Treatment:
1. Itraconazole 200–400 mg per day or ketoconazole 400 mg
per day
Severe
Treatment:
1. Amphotericin B 1 mg/kg per day for 2 weeks, then
itraconazole 200–400 mg per day or ketoconazole 400 mg
per day for a further 6 weeks provided improvement is
seen with amphotericin B Long-term maintenance for
patients with AIDS, itraconazole 200 mg per day –
relapse common if treatment discontinued
24. Type of Disease:
Pulmonary
Treatment:
1. Difficult to treat, relapse common Clinical
outcome improved by lobectomy and concomitant
amphotericin B 1 mg/kg per day, substituted by
itraconazole 400 mg per day upon improvement
2. For less severe disease, itraconazole 400 mg per
day from outsetDissemination risk
CNS
Treatment:
1. Refractory to antifungal therapy
25. Osteoarticular
Treatment:
1. Itraconazole 400 mg per day for 12 months or
longer: shorter courses lead to relapse
2. Fluconazole 400–800 mg per day is less effective;
use where there is itraconazole intolerance
Disseminated
Treatment:
1. Amphotericin B 1 mg/kg per day, continue until
total dose of 1–2 g administered
2. For less acute disease, itraconazole 400 mg per
day For AIDS patients, lifelong itraconazole to
prevent relapse
26. Type of disease:
Fusariosis (Fusarium species)
Treatment:
1. Correct neutropenia
2. Amphotericin B 1.0–1.5 mg/kg per day, or
liposomal amphotericin B 5 mg/kg per day
3. Flucytosine 25 mg/kg every 6 h for non-
responders(reversal of neutropenia
necessary for recovery)
27. Pseudallescheriosis (Pseudallescheria boydii,
Scedosporium apiospermum)
Treatment:
1. Surgical removal if possible
2. Miconazole 600 mg every 6 h i.v. usually best
initial reatment for seriously ill patients
(amphotericin B not effective)
3. Itraconazole 400 mg per day for other patients
Phaeohyphomycosis
Treatment:
1. Skin and subcutaneous tissue disease
2. Occasional dissemination: surgical excision
3. Itraconazole (oral solution) 400 mg per day
28. Trichosporonosis(Trichosporon species)
Treatment:
1. Correct neutropenia
2. Amphotericin B 1.0–1.5 mg/kg per day
Paecilomyces lilacinus
Treatment:
1. Itraconazole 200 mg per day 3 months.
Malassezia (Pityrosporum) septicemi
Treatment:
1. Remove intravascular catheter
2. Fluconazole 1 g i.v. per day if fungemia exists
29. Type of disease:
Primary pulmonary
No dissemination risk
Treatment:
1. Observe, or fluconazole 400 mg per day for 3–6
months.
Dissemination risk
Treatment:
1. Amphotericin B 0.5–0.7 mg/kg per day,
followed by fluconazole 400 mg for 6 months
30. Pulmonary cavity(uncomplicated) or fibronodular
disease
Treatment:
1. Surgical resection or closure
2. Fluconazole 400 mg per day or itraconazole 200
mg b.d. for at least 12 months. If no response,
amphotericin B 0.5–0.7 mg/kg/d
Progressive pulmonary or disseminated
(nonmeningeal)
immediately life threatening
Treatment:
1. Amphotericin B 1.0–1.5 mg/kg per day, to
achieve a total dose of 2500–3000 mg; switch to
fluconazole when disease is under control
31. slowly progressive or stable
Treatment:
1. Fluconazole 400–800 mg/kg per day, or
itraconazole 200 mg b.d.
Meningitis
Treatment:
1. Fluconazole 600–1200 mg per day
2. Itraconazole 400–600 mg per day
3. Amphotericin B directly into CSF together with
systemic therapy followed by oral fluconazole
600–1200 mg/kg/day
