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Project Title
Pharmaceutical Care Of Fungal Infection
A research presented by
Student Name:
Rasha Rasheed Abu Ali
Student No.:
9760092
Project supervisor Dr. Rafiq Abou Shaaban
June.2001
Ajman University Of Science and Technology
Abu Dhabi Branch
UAE
Research for this project was carried out by me during the period of Hospital Training-2 no.700443
(academic year 2000-2001)
Signed
Date June 17th,2001
ACKNOWLEDGMENTS
Sincere gratitude were extended to project supervisor Dr. Rafiq Abou Shabaan
from the pharmaceutical department for the continues follow up, constructive
criticism and valuable comments. The author indebted to Dr. Nadia to the support,
encouragement and fruitful accompaniment through out the training and presentation
of this project.
The author wishes to express special gratitude and thanks to those contributed
in this revolutionary, distinctive and advanced Hospital training II, namely Dr. Danna,
Dr Linda, Dr. Lamees and the staff of New Medical Center Hospital
2
INDEX
Description
Page No.
Section I
Introduction
4
Section II
Fungal infection
5
2.1
2.2
2.3
Immunosuppressed fungal infection
2.1.1
Aspergillosis
2.1.2
Mucormycosis
Systemic fungal infection
7
2.2.1
Histoplasmosis
2.2.2
Coccidioidomycosis
2.2.3
Blastomycosis
Skin fungal infection
11
2.3.1
Deep infection
2.3.2
Superficial fungal infection
Section III
5
Pharmaceutical Care
21
3.1
Patient Advice
21
3.2
Doctor Advice (Antifungal drugs)
23
3.3
Pharmacoeconomic
32
Section V
Clinical Cases
35
Section VI
Conclusion
46
Section VII
References
47
3
INTRODUCTION Section I
INTRODUCTION
A type of plant, fungi include molds and mushrooms. Spores of many fungi
everywhere in the environment. Often these spores float in the air. Of the wide variety
of spores that land on the skin or are inhaled into the lungs, some can cause minor
infection, which only rarely spread to other parts of the body. A few types of fungi,
such as the Candida strains, can live normally on body surfaces or in the intestine.
These normal body inhabitant only occasionally cause local infection of the skin,
vagina, or mouth, but seldom do more harm. Occasionally, however, certain strains of
fungi can produce severe infection of the lungs, the liver and the rest of the body.
As the population of immunosuppressed individuals increases, so do the
numbers and types of fungal infections noted in these patients. Although candidiasis
remains the most common fungal infection in immunosuppressed patients,
aspergillosis, zygomycosis, and other invasive filamentous fungal infections are a
major problem for certain groups of patients. The endemic mycoses, especially
histoplasmosis and coccidioidomycosis, constitute a risk for other groups of patients.
Many emerging fungal pathogens are resistant to the currently available antifungal
agents and, thus, pose a special risk for immunocompromised patients.
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FUNGAL INFECTIONS Section II
FUNGAL INFECTIONS
2.1
Immunosuppressed systemic fungal infection
2.1.1 Aspergillosis
Caused by the fungus Aspergillosis, is an infection affecting the lungs, it
occurs when Aspergillosis organisms on a body surface invade deeper tissues, such as
the ear canals or the lungs, particularly in person who has had tuberculosis or
bronchitis. A fungus ball can grow in the lungs. The ball is composed of a tangled
mass of fungus fibers, blood clotting fibers and white blood cells. It gradually
enlarges destroying lung tissue in the process. In people with suppressed body
defense, such as those who have had a heart a heart or liver transplant, aspergillosis
can spread through the blood stream to the brain and kidneys. It is recognized but
uncommon infection in people with AIDS.
Symptoms
Aspergillosis of the ear canal causes itching occasionally pain. Fluid draining
overnight from the ear may leave stain on the pillow.
The fungus ball in the lungs may cause no symptoms and be discovered only by a
chest x-ray. It may causes repeated coughing up of blood, and rarely severe, even
fatal, bleeding.
Infection of the deeper tissues makes the person very ill. Symptoms include fever,
chills, shock, delirium and blood clots. The person may develop kidney failure, liver
failure and breathing difficulties. Death can occur quickly
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Diagnosis and treatment:
The symptoms alone provide strong clues for making the diagnosis. If possible, a
sample of infected material is taken and sent to laboratory for culture. It may take a
few days for the fungus to grow enough to be identified, but treatment must be started
immediately, because the disease can kill quickly.
Aluminum acetate is used to bathe an infected ear canal. The fungus ball in the lung is
usually removed surgically. An antifungal drug, such as amphotericin B, usually is
infused intravenously. Ketoconazole and itraconazole are alternative drugs that are
taken orally for an infection of the deeper tissues. Some strains of Aspergillosis are
resistant to these drugs.
2.1.2 Mucormycosis
It is an infection caused by a fungus belonging to a large group of organism
called Mucorales
Mucormycosis of the nose and brain is a severe and usually fatal infection. This form
of Mucormycosis typically affects people whose body defenses are weakened by
disease such as uncontrolled diabetes.
Symptoms
Include pain, fever and an infection of the eye socket with a bulging of the affected
eye. Pus is discharged from the nose. The divider between the nostrils, the roof of the
mouth or the facial bones surrounding the eye socket or sinuses may be destroyed. A
brain infection may cause convulsion, an inability to speak properly and partial
paralysis.
Diagnosis and treatment:
The doctor may make the diagnosis by noting the persons symptoms and condition,
including a poor immunologic status or uncontrolled diabetes. The culture is hard to
grow, so it won’t be useful.
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A person with mucormycosis generally is treated with amphotercin B given
intravenously or injected directly into the spinal fluid. Infected tissues may be
removed by surgery. If the person also has diabetes, blood sugar levels are brought
down to within the normal range.
2.2
Systemic fungal infection
2.2.1 Histoplasmosis
An infection caused by Histolasma capsulatum that occurs mainly in the lungs
but can sometimes spread to all parts of the body.
The spores are present in the soil, farmers and others workingwith infected soil are
most likely to inhale the spores. Severe disease may result when large numbers of
spores are inhaled. People with human immunodeficiency virus (HIV) infection are
more likely to develop histoplasmosis, especially the form that spreads through out
the body.
Symptoms and Prognosis
Most people who are infected don’t have any symptoms. However, in those who show
signs of infection, histoplasmosis occurs in one of three forms, the acute form, the
progressive disseminated form, or the chronic cavitary form.
In the acute form, symptoms usually appear 3 to 21 days after a person inhales the
fungal spores. The person may feel sick and have a fever and a cough. Symptoms
usually disappear without treatment in 2 weeks and rarely lasts 6 weeks. This form of
histoplasmosis is seldom fatal.
The progressive disseminated form doesn’t normally affect healthy adults. It occurs in
infants and people who have an impaired immune system. Symptoms may worsen
either very slowly or extremely rapidly. The liver, spleen and lymph nodes may
enlarge. Less commonly, the infection causes ulcers in the mouth and intestine. In rare
cases the adrenal gland may be damages, causing Addison’s disease. Without
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treatment the progressive disseminated form of histoplasmosis is fatal in 90% of
people. Even with treatment, death may occur rapidly in people with AIDS.
The chronic cavitary form is a lung infection that develops gradually over several
weeks, producing a cough and increased difficulty in breathing. Symptoms include
weight loss, a feeling of illness and a mild fever. Most people recover without
treatment within 2 to 6 months. However, breathing difficulties may gradually
worsen, and some people may cough up blood, sometimes in large amounts. Lung
damage or bacterial invasion of the lungs eventually may cause death.
Diagnosis and treatment
To make the diagnosis, a doctor obtains samples from an infected person’s sputum,
lymph nodes, bone marrow, liver, mouth ulcers, urine or blood. These samples are
then sent to the laboratory for culture and analysis.
People with acute form of histoplasmosis rarely require drug treatment. Those with
the progressive disseminated form, however, often respond well to treatment with
amphotericin B given intravenously or to itraconazole given orally. In the chronic
cavitary form, itraconazole or amphotericin B may eliminate the fungus, although the
destruction caused by the infection leaves behind scar tissue. Breathing problems
similar to those caused by chronic obstructive pulmonary disease usually remain.
Therefore, treatment should begin as soon as possible to limit lung damage.
2.2.2 Coccidioidomycosis
An infection caused by Coccidioides immitis that usually affects the lungs.
Coccidioidomycosis occurs either as a mild lung infection that disappears without
treatment or a severe, progressive infection that spreads throughout the body and is
often fatal. The progressive form often a sign that the person has a compromised
immune system, usually because of AIDS.
The spores are found in the soil, farmers and others who work with soil are most
likely to inhale the spores and become infected. People who become infected while
traveling may not develop symptoms of the disease until after they leave the area.
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Symptoms
Most people with acute primary form of coccidioidomycosis have no symptoms. If
symptoms develop, they appear 1 to 3 weeks after the person becomes infected. The
symptoms are mild in most people and may include a fever, chest pain and chills. The
person also may cough up sputum and occasionally blood. Some people develop
desert rheumatism (a condition consisting of inflammation of the surface of the eye,
joints and the formation of skin nodules).
The progressive form of the disease is unusual and may develop weeks, months or
even years after the acute primary infection or after living in an area where the disease
is common. Symptoms include mild fever and losses of appetite, weight and strength.
The lungs infection may worsen, causing increased shortness of breath. The infection
also may spread from lungs to the bones, joints, liver, spleen, kidneys and the brain
and its lining.
Diagnosis
A doctor my suspect coccidioidomycosis if a person who lives in or has recently
traveled through and infected area develops these symptoms. Samples of sputum or
pus are taken from the infected person and sent to a laboratory for analysis. Blood
tests may reveal the presence of antibodies against the fungus. Such antibodies appear
early but disappear in the acute primary form of disease, the antibodies persist in the
progressive form.
Prognosis and treatment
The acute form of coccidioidomycosis usually clears up without treatment, and
recovery usually is complete. However, people with progressive form are treated with
intravenous amphotericin B or oral fluconazole. Alternatively, the doctor may treat
the infection with itraconazole or ketoconazole. Although drug treatment can be
effective in localized infection, such as those in skin, bones or joints, relapses often
occur after treatment is stopped. The most serious types of progressive
coccidioidomycosis are often fatal, especially meningitis. If a person develops
meningitis, fluconazole is used, alternatively, amphotericin B may be injected into the
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spinal fluid. Treatment must be continued for years, often for the rest of the patient’s
life. Untreated meningitis is always fatal.
2.2.3 Blastomycosis
An infection caused by the fungus Blastomyces dermatitidis. Blastomycosis is
primarily a lung infection, but occasionally it spread through the blood stream. Spores
probably enter the body through the respiratory tract when they are inhaled. It is not
known where in the environment the spores originate, but beaver huts where linked to
one out break. Most infections occur in the United States, chiefly in the south east and
the Mississippi River valley. Infections have also occurred in widely scattered area of
Africa. Men between the ages 20 and 40 are most commonly infected. The disease is
rare in people with AIDS.
Symptoms and diagnosis
Blastomycosis of the lungs begins gradually with a fever, chills and drenching sweats.
A cough that may or may not bring up sputum, chest pain and difficulty in breathing
may develop. Although the lung infection usually worsens slowly, it sometimes gets
better without treatment.
The disseminated form of blastomycosis may affect many areas of the body. A skin
infection may begin as small, raised bumps (papules), which may contain pus
(papulopustules). The papules and papulopustules last for a short time and spread
slowly. Raised, warty patches then develop, surrounded by tiny, painless abscesses.
Bones may develop painful swelling. In men, painful swelling of the epididymis or
deep discomfort from an infection of the prostate gland may occur.
A doctor can make diagnosis by examining a sample of sputum or infected tissue,
such as skin, under the microscope. If the fungi are seen, the sample can be cultured
and analyzed in a laboratory to verify the diagnosis.
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Treatment
Blastomycosis may be treated with intravenous amphotericin B or oral itraconazole.
With treatment, the person begins to feel better in a week and the fungus disappears
rapidly. Without treatment, the infection slowly worsens and lead to death.
2.3
Skin fungal infection
2.3.1 Deep fungal infections
Deep fungal infection e.g chromomycosis
is uncommon and is difficult to treat;
often
requiring
systemic
antifungal
agents; the management of patients with
such infections is best left to the
dermatologist and physician. However,
recognition of the condition is important
so that early treatment can be instituted
and irreversible complications averted.
2.3.2 Superficial fungal infections
These include the following,

Dermatophytosis (Ringworm)

Tinea versicolor

Candidiasis(Moniliasis)
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DERMATOPHYTOSIS (Tinea or Ringworm)
Dermatophytosis is probably the most common superficial fungal infection of the
skin. It is caused by a group of fungi, which are capable of metabolizing the keratin of
human epidermis, nails or hair. It is rare for true dermatophytes to penetrate into the
dermis or deeper body layers and when dermatophytes infections present with dermal
and subcutaneous reaction concomittent infection with other organisms, particularly
bacteria must be considered. There are 3 genera of dermatophytes causing
dermatophytosis, Microsporum, Trichophyton and Epidermophyton. Establishment
of dermatophyte infection of the skin depends on 2 factors, the virulence of the
infecting fungi and the physical condition of the skin (traumatised and macerated skin
are favourable to fungal growth).
Dermatophytosis is generally named and classified according to the site of infection
e.g. tinea capitis (scalp), tinea cruris (groin). Classification of the infection according
to reservoir e.g. animals (zoophilic), soil (geophilic) and human (anthropophilic) may
be useful in epidemiology and preventive measures against recurrent and spread of
infection. e.g. An outbreak or persistence of tinea capitis due to Microsporum cants (a
zoophilic) fungi may indicate infection from a pet (like, rabbits, cats, dog) at home
and eradication of infection in the pet may be necessary to prevent relapses.
CLINICAL FEATURES OF DERMATOPHYTOSIS ACCORDING TO SITE
Ringworm infections are usually classified according to the site of the lesion.
Tinea Capitis: This is cause by a variety of fungi e.g. M Audouinii, M Canis, the
former is usually contracted from other individuals and the latter from animals). Tinea
capitis is a childhood infection and is rare in adult. The penetration of the fungal
hyphae down into the hair shaft is characteristic and affects the hair and hair follicle.
Patches of non-scarring scaly alopecia with broken hairs is seen. Infection due to
zoophilic fungi tends to be more inflamed and in severe infections, boggy abscess
may develop (kerion). Tinea capitis is clinically differentiated from other alopecia e.g.
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alopecia areata, lupus erythematosus, and lichen planus by its scaly appearance and
the presence of broken hair.
Tinea Barbae: This is ringworm of the beard or moustache and often caused by
zoophilic fungi usually the Trichophyton genus. It is more common in the rural than
urban community. It is an infection of the adult and the lesion is usually inflamed
often with resulting scarring.
Tinea Corporis and Tinea Cruris: Tinea corporis is the term given to infection at
any site other than the scalp, groin, hands or feet. Although various fungi show some
preference in invading these other sites, tinea corporis may be caused by any of the
known dermatophyte species that makes the clinical picture rather variable. The
clinical picture can thus mimic a variety of dermatological conditions e.g. Pityriasis
rosea, erythrasma, secondary syphilis, psoriasis, lichen planus, drug eruptions, contact
dermatitis, discoid dermatitis etc.
Generally the lesions of tinea corporis are discrete, scaly and circular with a slowly
advancing border, which may show signs of inflammation. They tend to heal towards
the centre to give a characteristic annular appearance, which has been suggested as the
origin of the term "ringworm".
Tinea cruris is ringworm infection of the groin. Lesions usually occur on the inner
surface of the thighs and are scaly and erythematous, usually with a vesicular border.
T. metagrophytes, T rubrum or E. floccosum are common causative fungi. The former
tend to produce vesicular border and the latter two less vesicular but well marginated
borders.
Tinea Pedis (Feet) and Tinea Manuum (Hands): The fungi responsible are similar
to that in Tinea corporis but the conditions are often confused with eczema and
bacterial infections of the hands and feet.
Tinea pedis (athlete's foot) is one of the commonest and most troublesome
dermatophyte infections. Characteristically, the disease involves an area of peeling
and maceration between the toe clefts, although in extreme cases a large portion of the
foot may be involved. The condition is commonest in men, and it is believed to be
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spread in such areas as communal showers and changing rooms where small pieces of
skin are shed free.
Another common superficial dermatophytosis includes Tinea faciale which present
with characteristic scaly well defined lesions on the face where the helix of the ear is
often involved.
Tinea unguum is dermatophytic infection of the nail plate. Affected nail becomes
dystrophied, discoloured and hyperkeratotic. Onycholysis may be the initial
presentation.
Special mention must be made on T rubrum infection of the palms and soles. It is also
a common fungi infecting the hands, feet and nails. The clinical picture in T rubrum
infection may not be as scaly as those of tinea corporis and may present with
keratodermatous changes. Diagnosis can be confirmed by a deep fungal scraping from
the keratodermatous lesions.
Tinea incognito is tinea infection where the classical features of an active annular
erythematous, papulo-vesicular lesions become inapparent usually following
treatment with a topical steroid. In such condition the dermatophyte continues to
proliferate in the skin with its inflammatory response being suppressed by the topical
steroids. The lesion appears to be responding to steroid treatment but suffers a
rebound whenever the topical steroid is discontinued.
Diagnosis
Ideally the diagnosis of dermatophytosis should not be made until the causative
organism has been demonstrated. This can be easily achieved by scraping scales from
the active border of the skin lesions or from plucked hair in case of tinea capitis. The
scales are heated with KOH 10/lo on a microscope slide to dissolve away the keratin
and subsequently examined under the microscope.
Dermatophyte is identified as branching hyphae or mycelium which looks like
segmented spaghetti under the microscope.
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Wood's light can be useful in tinea capitis which fluoresces a brilliant green colour as
seen in a darkened room on infected scalp.
Treatment
Topical agents are usually adequate for limited dermatophyte infection of the skin.
Whitfield ointment (benzoic acid et salicylic acid) is the cheapest effective topical
agent here. However, it is greasy and may irritate inflamed skin. It is ineffective
against candida infection. The imidazoles are probably the most prescribed
antidermatophytic agent. There are several brands in the market e.g. Daktarin,
Canestan, Pevaryl, Travogen, etc. The efficacy of each imidazoles are generally
comparable. These imidazoles are advantageous to whitfield as they are more
acceptable and are effective against candida species and have mild antibacterial
property as well. They are more expensive. Other antidermatophytic agents including
the undecylate, tolnaftate (Tinaderm), naftifine (Exoderil), ciclopiroxolamine
(Batrafen) are also effective alternatives. Quinolines e.g. vioform and polyenes e.g.
nystatin are not effective against dermatophyte infection.
Combination creams containing imidazoles, steroids and antibiotics should be avoided
as they increase the risk of skin sensitization and skin reaction. Topical antibotics
especially neomycin and quinolines are among the common skin sensitizers in
Singapore. Imidazole in combination with a mild steroid e.g. hydrocortisone may
occasionally be useful as initial treatment for pruritic inflamed intertriginous
ringworm infection. However such combination cream should be discontinued and
substituted with plain antidermatophytes once the inflamed component clears.
Systemic treatment for dermatophytosis e.g. griseofulvin and ketoconazole are
indicated in extensive and recalcitrant dermatophyte infection and specific infection
such as tinea capitis, tinea barbae, tinea unguum. Griseofulvin is an effective and
commonly used oral agent against dermatophytosis. Griseofulvin should be taken in
doses of 500 mg to 1500 mg daily depending on body weight and should be taken
after meals for maximal absorption. Side effects include gastrointestinal symptoms
and photosensitivity. The duration of therapy depends on the location of
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dermatophytosis. Extensive tinea corporis usually require 4 to 6 weeks treatment and
nails infection requires 6 to 18 months therapy.
Oral ketoconazole is an effective alternative. It has the added advantage of having
anticandidal property. In a comparative study of treatment of dermatophytosis with
griseofulvin and ketoconazole in Singapore, the effficacy of both were found to be
similar but patients treated with oral ketoconazole appeared to have a slightly lower
relapse rate.
TINEA VERSICOLOR
Tinea versicolor is a common chronic superficial fungal infection caused by
Pityrosporum species, usually P orbiculare (Malassezia furfur).
Clinical Feature
The lesions are characterized discrete or concrescent scaly discoloured or
depigmented areas mainly on the upper trunk. The colour varies from dark brown to
grey and white. There is usually mild fine superficial scaliness. Occasionally the
lesion may be perifollicular. Other commonly affected sites include the arms, thighs,
face and hands. Pruritus may be troublesome especially with sweating but the
condition may be completely asymptomatic.
Differential diagnoses include vitiligo, melesma, idiopathic guttate hypomelanosis'
pityriasis alba, pityriasis rosea and post inflammatory hypopigmentations.
Diagnosis
Diagnosis can be easily confirmed by direct examination of skin scrapings.
Characteristic spherical, thick walled yeasts and coarse mycelium (often fragmented
to short filaments) is seen. The Parker Quink Ink/ KOH staining technique and
examination under the microscope is a simple procedure to identify the fungus.
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Treatment of tinea versicolor
Topical agents are the mainstay in the treatment of tinea versicolor. Recently oral
ketoconazole has been found to be useful for the treatment of severe/extensive and
tinea versicolor infection and infections recalcitrant to usual topical agents.
Common topical agents against tinea versicolor include sodium hyposulphide and
selenium sulphide containing preparations. The newer topical imidazoles and other
wide spectrum topical antifungal agents are as effective and cause less skin irritation
and easier to apply. However sodium hyposulphide and - selinium sulphide when
used as shampoos are effective prophylaxis against relapses. Initially sodium
hyposulphide and selenium sulphide preparations should be applied nightly for 5
nights. They can be subsequently used as prophylaxis by using them as shampoos
leaving the lotion on the scalp and skin for 10 to 15 minutes before bath once weekly
or fortnightly to prevent relapses.
Propylene glycol (50% in alcohol) is a cheap effective alternative topical agent.
The imidazoles and other newer broad spectrum antifungals such as tolnaftate,
naftifine, and ciclopiroxolamine available as cream and gel are effective and preferred
topical agents be used for localized infection but those with extensive tinea versicolor,
lotions and sprays are easier to use.
Oral ketoconazole in doses of 200 mg daily for 2 to 4 weeks is effective in the
treatment of severe/extensive tinea versicolor infection. Various treatment regimes
varying in doses of 200 mg weekly to 200 mg monthly have been reported to be
effective in preventing relapse but such regime may not be as effective as reported.
Great care should be taken when prescribing oral ketoconazole for this relatively
benign skin infection. Past history of liver disease and abnormal liver function test are
relative contraindications. Fulminating hepatitis has been reported to be associated
with oral ketoconazole and it should not be used to treat mild tinea versicolor.
Post infective hypopigmentation is a common sequelae following tinea versicolor
infection and this can persist for months to years. Such post infective
17
hypopigmentation does not indicate infection and does not require any treatment.
Recurrent tinea versicolor infection is common in our humid, tropical climate.
CANDIDIASIS
This is an infection caused by the yeast like fungus Candida albicans or occasionally
other species of Candida.
Clinical syndromes of candidiasis include:
Oral candidiasis (oral thrush): This is characterized by sharply defined patches of
creamy, crumbly, curd-like white pseudomembranous mucosal lesions which when
removed, leave an underlying erythematous base. The buccal epithelium, the tongue,
the gums or the palate may be affected. The condition occurs most commonly in the
first weeks of life and there is significant association with vaginal candida carriage in
the mother. Angular cheilitis and candida cheilitis produce erythematous fissures.
Candidiasis of the skin and genital mucous membrane: Most cases of cutaneous
candidiasis occur in the skin folds or where occlusion from clothing or medical
dressings produces abnormally moist conditions.
Candida intertrigo are typically erythematous, slightly moist lesions in skin folds. It
slowly spreads producing a characteristic fringed irregular edge and pustules
rupturing to give tiny erosions and peeling. Pustular or papular satellite lesions are
classical. Soreness, and itching may be intense. In babies the skin over the napkin
areas may be affected and occasionally associated with napkin eruption. When toe
webs are affected marked maceration with thick white horny layer is usually
prominen6. Differential diagnoses includes tinea infection, seborrhoeic dermatitis,
bacterial intertrigo, and flexural psoriasis. Skin scraping helps confirm diagnosis.
Candida vulvovaginitis and balanitis present with itching and soreness. The former
presents with thick creamy white discharge with characteristic cheesy plaques in the
vagina while the latter usually present with transient tiny papules with peeling
edges.and may be associated with soreness and irritation.
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Candida paronychia: This is chiefly found among housewives and those whose
hands are frequently immersed in water. Typically, several fingers are chronically
infected. The nailfold is red and swollen with loss of cuticle and detachment of
nailfold from the dorsal surface and the nail plate leading to pocketing. Nail dystrophy
with buckling of the nail plate and discoloration occur.
Chronic muco-cutaneous candidiasis: This is an uncommon condition where the
patient presents with persistent candida infection of the mouth, the skin and the nails
that are refractory to conventional topical therapy. It may be associated with a primary
defect in immune function.
Diagnosis
Candida can be recognised on skin scrapings and smears from mucosal lesions on
potassium
hydroxide
mount.
The
presence
of
budding
yeast
cells
and
pseudomycelium is evidence of active infection. The presence of spores alone is not
evidence of active infection as yeast is a common skin commensal. Candida infection
can be further confirmed by fungal cultures on Saborauds medium.
Treatment of Candidiasis
General Principle: It is important to be aware of predisposing factors which include
diabetes mellitus, anaemia, imparted immune status, malignancy, long term oral
antibiotics, oral steroids, cytotoxics, oral contraceptives, and pregnancy. In many
cases topical therapy alone is sufficient but consideration should be given to the
reduction of Candida reservoir in the mouth and gut in patients with recurrent
infections.
Topical Agents: The polyene antibiotics e.g. nystatin are highly effective against
Candida and most other yeast pathogens. The newer imidazoles eg, clotrimazole,
mico-nazole and econazole and other broad spectrum antifungal agents such as
tolnaftate, naftifine and ciclopirox etc. are effective alternatives. These are
advantageous over the polyenes as they are available in creams and lotion
preparations, are easier to apply and less messy. The affected areas should be kept
19
dry. The time honoured Castellani paint has the advantage over the other anticandidal
agents in affected toe webs and nail folds where secondary bacterial infection is
common. Non staining Castellani paint is more acceptable to patients. Powders
containing the newer antifungal powder e.g. imidazoles are useful adjunct on
intertriginous areas and as prophylaxis in those with recurrent infections. Whitfield
ointment is ineffective against candidiasis.
How to treat superficial fungal infection
1- Apply anti-fungal cream prescribed by your doctor on the affected areas 2-3
times a day for 3 weeks. Such creams include nystatin, tolnaftate, imidazole or
naftidine creams.
2- Do not stop using the medicine immediately after the infection has cleared.
Continues using it for at least 7 days after the infection appears to be cleared.
In the case of white spots, the white color remains even after the infection has
been successfully treated. However, this will gradually fade as the skin
recovers its normal coloring.
3- Oral anti-fungal tablets are needed for fungal infections affecting large areas.
Your doctor may prescribe them.
4- For prevention of white spots, use an anti-fungal shampoo once a month on
your scalp and body, leaving it on for 15 to 30 minutes before washing it off.
In the event of an infection, use this nightly for 7 days consecutively.
20
PHARMACEUTICAL CARE Section III
Pharmaceutical care
3.1
Patient Advice
3.1.1 Systemic infections
Mainly occurs in Immunosuppressed patients who are usually hospitalized, treatment
takes long period of time, which may lead to patient compliance.
Patients have to stick to the medication cause fungal infections are fatal in most of the
cases without the medication
Immunosuppressed patient at risk of fungal infection
 Hematologic malignancies
 Transplantation
 Acquired immunodeficiency syndrome
 Neutropenia associated with disease and drugs
 Collagen vascular disease (when treated with immunosuppresive drugs)
 ICU patient who had have GIT surgery or perforation, central venous catheter,
TPN, broad-spectrum antibiotics, burns, multi system organ failure, or are neonates.
 DM with ketoacidosis
 Iron chelating therapy with deferoxamine
 Chronic granulomatous disease
Factors contributing to development of fungal infection
 Exposure to the fungus.
 Inoculum delivered during exposure.
 Virulence of the fungus.
 Hosts immune status.
1- Underlying disease.
2- Immunosuppressive therapy.
3- Prior exposure to the fungus.
21
3.1.2 Skin infection
Causes of chronicity of superficial fungal infection
This include:
 Wrong diagnosis.
 Inadequate application of topical agents.
 Griseofulvin failure may be due to,
a. Poor compliance
b. Poor absorption and tissue levels. (should be taken after meals.)
c. Co-existent pathology
d. Resistance (rare)
 Constant reinfection
 Undetected, uncorrected predisposing factors
How to prevent superficial fungal infection
1- Fungus grows when the skin is warm and moist. The space between your toes,
the skin folds in the groin and the armpits must be kept dry to prevent such
fungal infection.
2- Do not walk barefoot in areas where the floor is wet - eg. bathroom, lavatory,
and swimming pool as the fungus tends to be present. Wear Slippers.
3- Avoid borrowing personal napkins, towels, combs and hair brushes as they
may be infected. Make sure you use your own personal items because fungal
infections are easily transmissible. Any item that comes into contact with the
affected areas must be sterilized before use.
4- Nylon socks and covered shoes make your feet sweat. Wear cotton socks to
absorb the sweat, or open-toe sandals if your feet sweat profusely.
5- Keep a healthy life-style with a balanced diet, exercise and have time for rest,
to increase your body's resistance. You will catch fungal infection easily if you
are weak.
22
3.2
Doctors Advice (Antifungals drugs)
TREATMENT OF FUNGAL INFECTION
Specialist treatment is required in most forms of systemic infections.
Aspergillosis, most common affects respiratory tract although, in severely
immunocompressed patients, invasive forms can affect the sinuses, heart, brain and
skin. Amphotericin by intravenous infusion is the drug of choice but response can be
variable, liposomal amphotericin or oral itraconazole are alternative in patient in
whom initial treatment has failed.
Candidiasis, Many superficial candidal infections are treated locally including
infections of the vagina and the skin.
Oropharyngeal candidiasis generally responds to topical therapy, an imidazole or
triazole antifungal are given by mouth for unresponsive infections. Fluconazole is
effective and is reliably absorbed.
For deep and disseminated candidiasis, amphotericin by intravenous infusion is used
alone or with flocytosine by intravenous infusion, an alternative is fluconazole given
alone particularly in AIDS patient in whom flocytosine is best avoided because of its
bone marrow toxicity.
Cryptococcosis, is uncommon but infection in immunocompromised, especially AIDS
patient, can be life threatening, cryptococcal meningitis is the most common form of
fungal meningitis. The treatment of choice is amphotericin by intravenous infusion
with or without flocytosine by intravenous infusion. Fluconazole is given alone is an
alternative particularly in AIDS patients with no disturbance of consciousness.
Following successful treatment, fluconazole can be used for prophylaxis against
relapse until immunity recovers.
Histoplasmosis, is rare in temperate climate, it can be life threatening, particularly in
HIV-infected persons. Itraconazole by mouth or ketoconazole by mouth can be used
for the treatment of immunocompetent patients with indolent non-meningeal infection
including chronic pulmonary histoplasmosis. Amphotericin by intravenous infusion is
preferred in patient with fluminant or severe infections.
Skin And Nail Infections, mild localized fungal infection of the skin (including tinea
corporis, tinea cruris, and tinea pedis) respond to topical therapy. Systemic therapy is
appropriate if topical therapy fails, if many areas are affected or if the site of infection
is difficult to treat such as in infections of the nails and the scalp.
23
Griseofulvin was used extensively in tinea of various sites but has now largely been
replaced by newer antifungals. Oral imidazole or triazole antifungals (particularly
itraconazole) and terbinafine are used more commonly because they have a broader
spectrum of activity and require a shorter duration of treatment.
Terbinafine and itraconazole have largely replaced griseofulvin for the systemic
treatment of onychomycosis, particularly of the toenail, terbinafine is considered to be
the drug of choice. Itraconazole can be administered as intermittent therapy.
Immunocompromised Patients, are at particular risk of fungal infections and may
receive antifungal drugs prophylactically, oral imidazole or triazole antifungals are
drug of choice. Fluconazole is more reliably absorbed than itraconazole and
ketoconazole, fluconazole is considered to be less toxic than ketoconazole on longterm use.
Most important points:
 In AIDS patient, flocytosine is best avoided because of its bone marrow toxicity.
 Fluconazole is given alone is an alternative particularly in AIDS patients with no
disturbance of consciousness.
 fluconazole can be used for prophylaxis against relapse until immunity recovers.
 Oral imidazole or triazole antifungals (particularly itraconazole) and terbinafine
are used more commonly because they have a broader spectrum of activity and
require a shorter duration of treatment.
 Fluconazole is more reliably absorbed than itraconazole and ketoconazole,
fluconazole is considered to be less toxic than ketoconazole on long-term use.
DRUG USED IN FUNGAL INFECTIONS
Polyene antifungals, they include amphotericin and nystatin, neither drug are
absorbed when given by mouth. They are used for oral, oropharyngeal and perioral
infection by local application in the mouth.
Amphotericin by intravenous infusion is used for the treatment of systemic fungal
infection and is active against most fungus and yeasts. It is highly protein bound and
penetrates poorly into body fluids and tissues. When given parentally amphotericin is
toxic and side effects are common. Lipid formulations of amphotericin are
significantly less toxic and are recommended when the conventional formulation of
24
amphotericin is contraindicated because of toxicity, especially nephrotoxicity, lipid
formulations are more expensive.
Nystatin is used principally for candida albicans infections of the skin and mucous
membranes, including oesophageal and intestinal candidas.
Imidazole antifungals, Clotrimazole, econazole, fenticonazole, sulconazole and
tioconazole are used for local treatment of vaginal candidiasis and for dermatophyte
infections.
Ketoconazole is better absorbed by mouth than other imidazole, it has been associated
with fatal hepatotoxicity, prescribers should weighthe potential benefits of
ketoconazole treatment against the risk of liver damage and should carefully monitor
patient both clinically and biochemically. It should not be used for superficial fungal
infections.
Miconazole can be used locally for oral infections, it is also effective in intestinal
infections. Systemic absorption may follow use of miconazole oral gel and may result
in significant drug interaction.
Triazole antifungals
Fluconzole is very well absorbed after oral administration. It also achieves good
penetration into the cerebrospinal fluids to treat fungal meningitis.
Itraconazole is active against a wide range of dermatophytes. It requires and acid
environment in the stomach for optimal absorption.
Itraconazole has been associated with liver damage and should not be given to
patients with history of liver disease, fluconazole is less frequently associated with
hepatotoxicity.
Other antifungals.
Flucytosine is often used with amphotericin in a synergistic combination. Bone
marrow depression can occur which limits its use, particularly in AIDS patients,
weekly blood count are necessary during prolonged therapy. Resistance to flucytosine
can develop during therapy and sensitivity testing is essential before and during
treatment.
Griseofulvin is effective for widespread or intractable dermatophyte infections but has
been suppressed by newer antifungals, particularly for nail infections. It is usually
well tolerated and is licensed for use in children. Duration of the therapy is dependent
on the site of infection and may be required for a number of months.
25
Terbinafine is the drug of choice for fungal nail infections where oral treatment is
considered appropriate.
Most important points:
 Amphotericin and nystatin, neither drug are absorbed when given by mouth.
 Lipid formulations of amphotericin are significantly less toxic and are
recommended when the conventional formulation of amphotericin is contraindicated
because of toxicity, especially nephrotoxicity.
 Ketoconazole is better absorbed by mouth than other imidazole, it has been
associated with fatal hepatotoxicity, carefully monitor patient both clinically and
biochemically.
 Fluconazole has good penetration into the cerebrospinal fluids.
 Itraconazole requires and acid environment in the stomach for optimal absorption.
Associated with liver damage and should not be given to patients with history of liver
disease, fluconazole is less frequently associated with hepatotoxicity.
 Flucytosine is often used with amphotericin in a synergistic combination. Bone
marrow depression can occur, weekly blood counts are necessary during prolonged
therapy. Resistance to flucytosine can develop during therapy and sensitivity testing is
essential before and during treatment.
 Griseofulvin is usually well tolerated and is licensed for use in children.
Drug
Contraindications
Side effects
Interaction
Anorexia, nausea,
Cardiac glycoside increase
pregnancy, breast
vomiting,
toxicity if hypokalaemia
feeding, hepatic
diarrhea,
occurs. Ciclosporin
disease
epigastric pain,
increase risk of
febrile reaction,
nephrotoxicity.
headache, muscle
Corticosteroids increase
and joints pain,
risk of hypokalaemia.
anemia,
Tacrlimus increase risk of
disturbance of
nephrotoxicity. Diuretics
renal function.
increase risk of
Amphotericin Renal impairment,
hypokalaemia with loop
26
and thiazide diuretics.
Fluconazole
Renal impairment,
Nausea,
Plasma concentration of
pregnancy, breast
abdominal
celecoxib is increased.
feeding, hepatic
discomfort,
Rifampicin accelerate
disease
diarrhea,
metabolism. Rifabutin
flatulence,
plasma concentration is
abnormal liver
increased. Affect of
enzyme, rash,
acenocoumarol and
angioedema,
warfarin are enhanced.
anaphylaxis,
Manufacturer of reboxetine
bullous lesions,
advises to avoid with it.
toxic epidermal
Plasma concentration of
necrolysis,
sulphonylureas is increased
Stevens-Johnson
Effect of phenytoin
syndrome
enhanced. Antagonize the
reported, severe
affect of amphotericin.
cutaneous
Inhibit terfenadine
reactions in AIDS
metabolism. Risk of
patients
ventricular arrhythmias if
given with pimozide.
Increased plasma
concentration of
zidovudine
Increased plasma
concentration by ritonavir.
Increased plasma
concentration of
saquinavir. Increased
plasma concentration of
midazolam. Increased
plasma concentration of
ciclosporin. Increased
plasma concentration by
27
hydrochlorothiazide.
Increased risk of myopathy
with simvastatin &
atrovastatin. Contraceptive
failure. Increased plasmatacrolimus concentration.
Increased plasmatheophylline conc.
Flucytosine
Renal impairment,
Nausea, vomiting,
Renal excretion reduced
elderly, blood
diarrhea, rashes,
and cellular uptake is
disorder, liver
confusion, vertigo
increased by amphotericin
disease, pregnancy,
(toxicity may increase).
breast feeding
Cytarabine reduces plasma
concentration.
Griseofulvin
Severe liver
Headache, nausea, Metabolism of
disease, lupus
vomiting, rashes,
acenocoumarol and
erythematosus and
photosensitivity,
warfarin accelerated.
related condition,
dizziness, fatigue,
Absorption reduced by
porphyria,
agranulocytosis,
phenobarbital. Plasma-
pregnancy.
leucopoenia
ciclosporin concentration
is reduced. Contraceptive
metabolism increased.
Itraconazole
Liver disease,
Nausea,
Antacid reduce the
peripheral
abdominal pain,
absorption. Increase
neuropathy,
dyspepsia,
plasma concentration of
pregnancy and
constipation,
quinidine. Rifampicin
breast-feeding.
headache,
accelerate metabolism.
dizziness, allergic
Plasma concentration of
reaction, raised
rifabutin increased. Affect
liver enzymes,
of acenocoumarol and
menstrual
warfarin enhanced. Plasma
disorder, hepatitis
concentration is decreased
28
and cholestatic
by phenytoin. Inhibit
jaundince,
terfenadine metabolism.
peripheral
Manufacturer of
neuropathy,
tolterodine advice avoid
Stevens-Johnson
concomitant use with it.
syndrome
Plasma indinavir
reported,
concentration increases.
hypokalaemia,
Amprenavir increased
oedema and hair
plasma concentration.
loss in prolonged
Plasma concentration of
use has been
midazolam is increased.
reported.
Inhibit the metabolism of
felodipine and other
dihydropyridines. Plasma
concentration of digoxin is
increased. Ciclosporin
metabolism is inhibited.
Methylprednisolone
metabolism is inhibited.
Vincristine metabolism is
inhibited. Increase the risk
of myopathy with
simvastatin and
atorvastatin. Cerivastatin
plasma concentration is
increased. Contraceptive
fails. Increase plasmasildenafil concentration.
Absorption reduced by H2
antagonist and proton
pump inhibitor.
Ketoconazole
Hepatic
Nausea, vomiting,
29
Alfentanil metabolism
impairment,
abdominal pain,
inhibited, antacid reduces
pregnancy, breast
rashes, urticaria
the absorption, rifampicine
feeding, porphoria
pruritus, rarely
increases the metabolism,
angioedema,
isoniazid reduces the
thrombocytopenea plasma concentration,
paraesthesia,
acenocoumarol and
photophobia,
warfarin effect is inhanced,
dizziness,
manufacturer of reboxetine
alopecia,
advices to avoid, phenytoin
gynaecomastia,
reduces the plasma
and oligospermia,
concentration, increased
fatal liver damage
plasma-loratadine
concentration, inhibit the
metabolism of mizolastine,
manufacturer advice to
avoid with tolterodine
because it reduces
absorption, with pimozide
risk of ventricular
arrhythmias, inhibit the
metabolism of indinavir,
nevirapine, ritonavir and
saquinavir, plasma
concentration of
midazolam is increased,
inhibit the metabolism of
feldopine, inhibit the
metabolism of
corticosteroids and
ciclosporin, increase the
risk of myopathy with
simvastatin and
atorvastatin, contraceptive
30
failure, increase plasma
sildenafil concentration,
increase plasma tacrolimus
conc., increase plasma
theophylline concentration,
absorption is reduced by
H2 antagonist, proton
pump inhibitor and
sucralfate
Miconazole
Hepatic
Nausea, vomiting,
Acenocoumarol and
impairment,
diarrhea, rarely
warfarin effect is inhanced,
pregnancy and
allergic reaction
manufacturer of reboxetine
breast feeding
advices to avoid, increased
plasma-sulphonylureas
concentration, avoid
concomitant use with
glipizide, phenytoin
enhance the effect, inhibit
metabolism of terfanidine,
with pimozide risk of
ventricular arrhythmias,
ritonavir increases the
plasma concentration,
inhibit the metabolism of
ciclosporin, increase the
risk of myopathy with
simvastatin and
atorvastatin, increase
plasma tacrolimus
concentration
Nystatin
--------
Nausea, vomiting,
diarrhea, oral
31
--------
irritation and
sensitization, rash
Terbinafine
Hepatic and renal
Abdominal
Refampicin increases the
impairment,
discomfort,
plasma concentration,
pregnancy and
anorexia, nausea,
plasma concentration
breast feeding,
diarrhea,
increased by cimetidine
headache, rash
and urticaria
occasionally with
athralgia or
myalgia
3.3
Pharmacoeconomic
Introduction
Antimicrobial drug management typically centers on two initiatives: controlling costs
and controlling antimicrobial resistance. In the past two decades, emphasis has been
placed on containing the cost of antimicrobial agents; the humanistic, environmental,
and
economic
impacts
of
antimicrobial
resistance
have
been
secondary
considerations. We cannot just reduce drug costs without looking in depth at the
problems arising with current patterns of drug selection.
Today, when patients are not responding to a particular antimicrobial, the response of
many practitioners is simply to switch to another drug and wait to see if it is
successful or ineffective. Selection of therapeutic alternatives without adherence to a
program that has optimal clinical and bacteriological responses as primary goals, or
without a rationale based on data from the medical literature, may promote
antimicrobial resistance. Attempts to pick cheaper alternatives can produce cost
shifting rather than cost containment.
32
Polyenes - Amphotericin B
Macrolide ring - series of double bonds
Mechanisms - bind to ergosterol in the fungal cell membrane
Administration - poorly soluble , prepare suspension, no electrolytes, slowly infuse iv
Toxicity -- absorbs to renal tissues, causes necrosis, loss of renal function
1. Fungilin: tablets 100mg 56-tablet pack = Dhs. 43.3
2. Fungizone: intravenous infusion powder, 50mg vial = Dhs. 19.2
Lipid formulation
3. Abelcet: intravenous infusion 5mg/ml, 10ml = Dhs. 104
4. AmBisone: intravenous infusion powder, 50mg vial = Dhs. 720.1
5. Amphocil: intravenous infusion powder, 50mg vial = Dhs. 720.1
Imidazole Drugs
Related family of drugs - all contain an imidazole, or triazole, ring structure
Ketoconazole, fluconazole, miconazole, itraconazole
Pharmacokinetics vary - in general easier to give, less toxic, sometimes less effective,
Inhibit ergosterol synthesis
Use for combined therapy with amphotericin
1. Diflucan: 50mg fluconazole, 7 capsule pack = Dhs. 86.4
2. Nizoral: 200mg ketoconazole, 30 tablets pack = Dhs. 81.6
3. Sporanox: 100mg itaconazole, 4 capsule pack = Dhs. 29.7
4. Daktarin: oral gel miconazole. 15g tube = Dhs. 11.8
Flucytosine
Converted to 5-fluoropyrimidine by fungal cells -- inhibits nucleic acid synthesis
Chief use -- cryptococcal meningitis
Crosses blood-brain barrier
Resistance can develop
Ancotil: intravenous infusion, flucytosine 10mg/ml, 250ml = Dhs. 185.6
33
Iodides
KI -- given orally or by injection
Seems effective for various types of chronic granulomatous infections
Mechanism unknown -- not anti-fungal in vitro
Causes iodide toxicity -- but is reversible
Low cost
Griseofulvin
Dermatophyte infection
Give with fatty meal -- increases absorption
Concentrates in keratinized epithelium
Inhibits fungal cell wall metabolism
Usually non-toxic - can cause GI disturbances
Contraindicated in pregnancy -- can be teratogenic
Grisovin: 500mg tablet 20 tablet = Dhs. 9.1
34
CLINICAL CASES Section IV
Clinical Cases
Case 1
Ten year old who first noticed discoloration of tongue approximately one
week ago. Aside from the discolored tongue, he is otherwise healthy, feels well and is
without complaints.
Aspergillus niger
Saprophytic fungus that colonizes the upper
respiratory tract in immunocompromised
individuals and occasionally in normal hosts on
broad-spectrum antimicrobials and birth control
pills
Most common sites for colonization are oral
pharynx and external auditory canal.
Rarely, if ever, causes invasive disease.
Comment:
 Patient details: 10 years old boy.
 Signs & Symptoms: discoloration of tongue one week ago.
 Diagnosis: Aspergillus niger.
 Medication history: none
 Suggested treatment: The fungus ball in the lung is usually removed surgically.
An antifungal drug, such as amphotericin B, usually is infused intravenously.
Ketoconazole and itraconazole are alternative drugs that are taken orally for an
infection of the deeper tissues. Some strains of Aspergillosis are resistant to these
drugs.
35
Case 2
Eight years old who had trauma (rock from a sling shot) to his head
approximately one month ago. Has been treated for 10 days with twice daily oral
penicillin without a significant response.
Kerion
Exaggerated host response to tinea capitis.
Varies from inflammatory pustular lesions to boggy,
indurated fluctuant mass; lesions may be multiple or
solitary
Hair loss is invariably present
Rx: Don’t aspirate!
Oral antifungals
Aluminum acetate compresses if weepy
Comment:
 Patient details: 8 years old.
 Signs &Symptoms: alopecia and trauma one month ago.
 Medication history: Has been treated for 10 days with twice daily oral penicillin.
 Diagnosis: Kerion.
 Suggested treatment: griseofulvin and ketoconazole are indicated in extensive and
recalcitrant dermatophyte infection and specific infection such as tinea capitis.
36
Case 3
Six year old who sustained a puncture wound to his forearm approximately 4
months ago. He developed a purulent lesion at the site for which he was treated with
an oral cephalosporin. The parents think that there was some improvement but the
lesion has persisted with periodic drainage: he has had 5 courses of oral antibiotic
therapy with little response.
Sporotrichosis
Subacute to chronic fungal infection
Superficial and systemic clinical expression
Lymphocutaneous form most common
Should be considered in differential of any
nonhealing skin lesion
Rx: Potassium iodide
Comments:
 Patient Details: 6 years old
 Signs & Symptoms: sustained puncture wound to his forearm approximately 4
months ago, developed purulent lesion and periodic drainage.
 Medication History: treated with an oral cephalosporin and had had 5 courses of
oral antibiotic.
 Diagnosis: Sporotrichosis.
 Suggested Treatment: preferred to be treated with itraconazole taken orally
because potassium iodide is not as effective and causes side effects in most people,
such as rash, runny nose, inflammation of the eyes, mouth and throat.
37
38