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ABSTRACT

Tinea capitis is a fungal infection of the scalp and hair caused by dermatophytes. It
occurs in all age groups but predominantly found in children. The antifungal activities
such as MIC, MFC and rate of kill of fluconazole, terbinafine, lauric acid and sodium
propionate alone and in admixture against dermatophyte isolates from school children
with tinea capitis in L. E. A. primary school, Mando, Kaduna, Nigeria were assessed.
T. mentagrophyte, T. tonsuran, T. rubrum, Trichophyton species M. canis, P. furfur. P.
hortei were isolated from the school children. The trichophyton species had the
highest order of prevalence (56.67%) followed by P. furfur (20%) while P. hortei was
(13.33%) and M.canis was (10%).
The Minimum Inhibitory Concentration (MIC) and the Minimum Fungicidal
Concentration (MFC) of fluconazole ranges were (0.5- 1.0mg/ml) and (1.00 –
8.00mg/ml) respectively against the test organisms. T. mentagrophyte (isolate number
18) was found to be the most resistant of the organisms that were isolated from the
school children. The order of potent activity of the test antifungal agents was
fluconazole, terbinafine, lauric acid and sodium propionate. The combination of the
test antifungal agents investigated was found to be synergistic. Terbinafine and
Sodium propionate combination produced marked synergistic action (FIC=0.57)
against the most resistant dermatophyte isolate.
Terbinafine (10mg/ml) and Sodium propionate (200mg/ml) after 60mins contact time
produced 5.2 and 4.3 log reduction of 1.025 x 108 spores/ml of resistant T.
mentagrophyte. The combination of Terbinafine (10mg/ml) and Sodium propionate
(200mg/ml) effected 100% kill of 1.02 x108 spores/ml of resistant T. mentagrophyte
after 20 minutes contact time. Thus the use of terbinafine/ sodium propionate
combination therapy for dermatophyte infection seem promising

 

 

TABLE OF CONTENTS

Declaration ———————————————————————————-
Certification———————————————————————————–
Dedication————————————————————————————-
Acknowledgement—————————————————————————
Abstract—————————————————————————————–
List of Tables——————————————————————————–
List of Figures ———————————————————————————
List of Appendices
CHAPTER ONE
1.0 INTRODUCTION———————————————————————
1.1 DERMATOPHYTES————————————————————–
1.1.1 MORPHOLOGY AND IDENTIFICATION OF DERMATOPHYTES—
1.2 TINEA CAPITIS———————————————————————-
1.2.1 PATHOPHYSIOLOGY OF TINEA CAPITIS———————————-
1.2.2 EPIDEMIOLOGY OF TINEA CAPITIS—————————————-
1.2.3 FREQUENCY OF TINEA CAPITIS——————————————–
1.2.4 GEOGRAPHIC DISTRIBUTION OF TINEA CAPITIS———————
1.2.5 CLINICAL MANIFESTATION OF TINEA CAPITIS————————-
1.2.6 DIAGNOSIS OF TINEA CAPITIS————————————————
1.3 ANTIFUNGAL AGENT—————————————————————-
10
1.4 TREATMENT OF TINEA CAPITIS————————————————-
1.5 DRUG RESISTANCE IN FUNGI——————————————————-
1.5.1. PREVENTION AND CONTROL OF ANTIFUNGAL RESISTANCE———–
1.6 METHOD FOR STUDYING ANTIFUNGAL COMBINATIONS—————–
1.7 AIMS AND OBJECTIVES—————————————————————-
CHAPTER TWO
2.0 MATERIALS AND METHODOLOGY————————————————–
2.1 MATERIALS ——————————————————————————–
2.1.1 ORGANISMS USED———————————————————————–
2.1.2 CULTURE MEDIA AND SUSPENDING MEDIA————————————
2.1.3 ANTIFUNGAL AGENTS TESTED——————————————————
2.1.4 OTHER MATERIALS———————————————————————-
2.2 METHODOLOGY—————————————————————————
2.2.1 PREPARATION OF MEDIA————————————————————-
2.2.2 COLLECTION OF SAMPLES AND ISOLATION OF TEST FUNGI SPORE.–
2.2.3 INOCULATION OF TINEA CAPITIS SAMPLES ON SDA————————-
2.2.4 MICROSCOPY AND IDENTIFICATION———————————————
2.3 PREPARATION OF SPORE SUSPENSION—————————————-
2.4 PREPARATION OF ANTIFUNGAL AGENTS—————————————
2.4.1 FLUCONAZOLE—————————————————————————-
2.4.2 TERBINAFINE——————————————————————————
11
2.4.3 LAURIC ACID——————————————————————————–
2.4.4 SODIUM PROPIONATE——————————————————————
2.5 DETERMINATION OF MINIMUM INHIBITORY CONCENTRATION (MIC) OF
TEST ANTIFUNGAL AGENTS. ————————————————————
2.6 DETERMINATION OF MINIMUM FUNGICIDAL CONCENTRATION (MFC)–
2.7 DETERMINATION OF THE RATE OF KILL—————————————–
CHAPTER THREE
3.0 RESULT————————————————————————————–
3.1 FUNGI ISOLATES ————————————————————————
3.2 MINIMUM INHIBITORY CONCENTRATION (MIC) & MINIMUM FUNGICIDAL
CONCENTRATION (MFC) OF THE TEST ANTIFUNGAL AGENTS AGAINST
ISOLATES FROM THE SCHOOL CHILDREN———————————
3.3 DETERMINATION OF MIC & MFC OF THE TEST ANTIFUNGAL AGENTS IN
ADMIXTURES ———————————————————————————–
3.4 RATE OF KILL OF TEST ANTIFUNGAL AGENTS ALONE AND IN ADMIXTURE
AGAINST RESISTANT T. mentagrophyte
CHAPTER FOUR
4.0 DISCUSSION AND CONCLUSION—————————————————-
4.1 GENERAL DISCUSSION——-
4.2 PREVALENCE OF DERMATOPHYTIC INFECTION IN L. E. A. PRIMARY
SCHOOL MANDO, KADUNA————
4.3 MICs AND MFCs OF THE TEST ANTIFUNGAL AGENTS AGAINST
ISOLATES———
12
4.4 FUNGICIDAL EFFECTS OF THE TEST AGENTS IN ADMIXTURE ——-
REFERENCES—————————————————————————————
13

 

 

CHAPTER ONE

1.0 INTRODUCTION
The body normally hosts a variety of microorganisms including bacteria, mold-like
fungi (dermatophytes) and yeast-like fungi (such as candida). Some of these are
useful to the body. Others may under proper conditions multiply rapidly and cause
infection. Fungal skin infections are caused by microscopic fungi that flourish on the
human skin. Fungal infection has emerged as a significant clinical problem in recent
years (NCCLS 1997). Due to the increasing frequency of fungal infections, mycology
is today undergoing renaissance. The incidence of fungal infection has markedly
increased in recent years. Several factors have contributed to this. These include
greater use of immunosuppressive drugs, prolonged use of broad-spectrum
antibiotics, widespread use of in dwelling catheter and the Acquired Immunodeficiency
Syndrome (AIDS)
Fungal infection is divided into systemic infection and dermatophycoses. Recognition
and appropriate treatment of these infections reduce both morbidity and discomfort
and lessen the possibility of transmission (Cohn 1992).
Dermatophyte infections are classified according to the affected body site such as
Tinea Capitis (scalp and hair), Tinea Barbae (beard area), Tinea Corporis (skin other
than bearded area, scalp, groin, hands and feet) Tinea Cruris (groin perineal area and
perineum), Tinea Pedis (feet), Tinea manuum (hands) and Tinea unguuim (nails). The
estimated lifetime risk of acquiring a dermatophyte infection is between 10 and 20
percent (Drake et al 1996).
17
1.1 DERMATOPHYTES
Dermatophytes are fungi that can cause infections of the skin, hair, and nails due to
their ability to utilize keratin. The organisms colonize the keratin tissues and
inflammation is caused by host response to metabolic bye-products. These infections
are known as ringworm or tinea, in association with the infected body part.
Occasionally, the organisms do invade the subcutaneous tissues, resulting in kerion
development (St Germain and Summerbell, 1996).
The dermatophytic causative organisms are transmitted by either direct contact with
infected host (human or animal) or indirect contact with infected exfoliated skin or hair
in combs, hairbrushes, clothing, furniture, theatre seats, caps, bed linens, towels, hotel
rugs, and locker room floors (St Germain and Summerbell, 1996).
Depending on the species, the organisms may be viable in the environment for up to
15 months. There is an increased susceptibility to infection when there is a preexisting
injury to the skin such as scars, burns, excessive temperature and humidity (St
Germain and Summerbell, 1996).
Dermatophytes cause a variety of clinical conditions. They are among the most
common infectious agents of humans. Collectively, the group of diseases is termed
dermatophytosis. From the site of infection the fungal hyphae grow centrifugally in the
stratum corneum. The fungus continues downward growth into the hair invading
keratin as it is formed. The zone of involvement extends upward at the rate at which
the hair grows and it is visible above the skin surface by days 12-14. Infected hairs
18
are brittle and by the third week broken hair are evident (St Germain and Summerbell,
1996).
The infection continues (for 8-10 weeks) to spread in the stratum corneum to involve
other hairs at which point, the infected area is approximately 3.5-7.0 cm in diameter.
The spontaneous cure of naturally occurring infection at puberty is a familiar clinical
observation(St Germain and Summerbell, 1996).
Dermatophytes are classified as anthropophilic, zoophilic or geophilic according to
their normal habitat.
 Anthropophilic dermatophytes are restricted to human hosts and produce a
mild, chronic inflammation.
 Zoophilic organisms are found in animals and cause marked inflammatory
reactions in humans who have contact with infected cats, dogs, cattle, horses,
birds, or other animals. This is followed by a rapid termination of the infection.
 Geophilic species are usually recovered from the soil but occasionally infect
humans and animals. They cause a marked inflammatory reaction, which limits
the spread of the infection and may lead to a spontaneous cure but may also
leave scars.
1.1.1 MORPHOLOGY AND IDENTIFICATION OF DERMATOPHYTES
They are classified into three genera: Epidermophyton, Microsporum and
Trichophyton. In keratinized tissue, these form only hyphae and arthrospores. In
culture, they develop characteristic colonies and conidia, by means of which they can
be divided into species. Sexual spores of some species have been found. Most
19
dermatophytes are worldwide in distribution, but some species show a higher
incidence in certain regions than in others (e.g. Trichophyton schoenleinii in the
mediterraneian, Trichophyton rubrum in tropical climates).
Representative colonies form on sabouraud dextrose agar at room temperature.
Conidia formation may be observed by means of slide cultures. Sabouraud medium is
suitable for the isolation of dermatophytes with the addition of cycloheximide, which
inhibits many common non-pathogenic fungi contaminants.
Characteristics of more commonly isolated Dermatophytes are shown in table 1.0
 TRICHOPHYTON
Trichophyton is a dermatophyte which inhabits the soil, humans or animals. Based on
its natural habitats, the genus includes anthropophilic, zoophilic, and geophilic
species. Some species are cosmopolitan. Others have a restricted geographic
distribution. Trichophyton concentricum, for example, is endemic at Pacific Islands,
Southeast Asia, and Central America. Trichophyton is one of the leading causes of
hair, skin, and nail infections in humans (Arenas et al 1995).
The genus Trichophyton has several species. Most common are Trichophyton
mentagrophytes, Trichophyton rubrum, Trichophyton schoenleinii, Trichophyton
tonsurans, Trichophyton verrucosum, and Trichophyton violaceum. Trichophyton
rubrum is the commonest causative agent of dermatophytoses worldwide (Arenas et
al 1995). Trichophyton species may cause invasive infections in immunocompromised
hosts (Squeo et al 1998).
The growth rate of Trichophyton colonies is slow to moderately rapid. The texture is
waxy, glabrous to cottony. From the front, the color is white to bright yellowish beige or
20
red violet. Reverse is pale, yellowish, brown, or reddish-brown (Dehoog et al 2000;
Larone, 1995; St Germain and Summerbell 1996; Sutton et al 1998).
Trichophyton have septate, hyaline hyphae, conidiophores, microconidia,
macroconidia, and arthroconidia. Chlamydospores may also be produced.
Conidiophores are poorly differentiated from the hyphae. Miroconidia (also known as
the microaleuriconidia) are one-celled and round or pyriform in shape. They are
numerous and are solitary or arranged in clusters. Microconidia are often the
predominant type of conidia produced by Trichophyton. Macroconidia (also known as
the macroaleuriconidia) are multicellular (2- or more-celled), smooth-, thin- or thickwalled
and cylindrical, clavate or cigar-shaped. They are usually not formed or
produced in very few numbers. Some species may be sterile and the use of specific
media is required to induce sporulation (Dehoog et al 2000; Larone, 1995; St Germain
and Summerbell 1996; Sutton et al 1998). Trichophyton differs from Microsporum and
Epidermophyton by having cylindrical, clavate to cigar-shaped, thin-walled or thickwalled,
smooth macroconidia.
21
Microconidia and a terminal macroconidium of T. rubrum
 MICROSPORUM
Microsporum is a filamentous keratinophilic fungus included in the group of
dermatophytes. The natural habitat of some of the Microsporum spp. is soil (the
geophilic species), others primarily affect various animals (the zoophilic species) or
human (the anthropophilic species). Some species are isolated from both soil and
animals (geophilic and zoophilic). Most of the Microsporum spp. are widely distributed
in the world while some have restricted geographic distribution. Microsporum is the
asexual state of the fungus and the telemorph phase is referred to as genus
Arthroderma (Caffara and Scagliarini, 1999; Pier and Morielli, 1998; St-Germain and
Summerbell 1996).
22
The genus Microsporum includes 17 conventional species. Among these, the most
significant are: M. canis, M. audouinii, M. nanum, M. gypseum, M. cookie, M.
distortum, M. ferrugineum, M. gallinae
Microsporum is one of the three genera that cause dermatophytosis. Dermatophytosis
is a general term used to define the infection in hair, skin or nails due to any
dermatophyte species. Notably, Microsporum spp. mostly infect the hair and skin,
except for Microsporum persicolor which does not infect hair. Nail infections are very
rare (Aly,1999; Collier et al, 1998; Elewski, 2000; Frieden, 1999; Romano, 1998).
Microsporum colonies are glabrous, downy, wooly or powdery. The growth on
Sabouraud dextrose agar at 25°C may be slow or rapid and the diameter of the colony
varies between 1 to 9 cm after 7 days of incubation. The color of the colony varies
depending on the species. It may be white to beige or yellow to cinnamon. From the
reverse, it may be yellow to red-brown (St-Germain and Summerbell 1996).
Microsporum spp. produces septate hyphae, microaleurioconidia, and
macroaleurioconidia. Conidiophores are hyphae-like. Microaleuriconidia are
unicellular, solitary, oval to clavate in shape, smooth, hyaline and thin-walled.
Macroaleuriconidia are hyaline, echinulate to roughened, thin- to thick-walled, typically
fusiform (spindle in shape) and multicellular (2-15 cells). They often have an annular
frill. Inoculation on specific media, such as potato dextrose agar or Sabouraud
dextrose agar supplemented with 3 to 5% sodium chloride may be required to
stimulate macroconidia production of some strains (St-Germain and Summerbell
1996).
23
Microsporum differs from Trichophyton and Epidermophyton by having spindle-shaped
macroconidia with echinulate to rough walls (St-Germain and Summerbell 1996).
Macroconidia of M. canis. The septal wall is thinner than the outer wall
 EPIDERMOPHYTON
Epidermophyton is a filamentous fungus and one of the three fungal genera classified
as dermatophytes. It is distributed worldwide. Man is the primary host of
Epidermophyton floccosum, the only species which is pathogenic. The natural habitat
of the related but the nonpathogenic species Epidermophyton stockdaleae is soil
(Dehoog et al 1998; Larone, 1995; Sutton et al 1998).
The genus Epidermophyton contains two species; Epidermophyton floccosum and
Epidermophyton stockdaleae. E. stockdaleae is known to be nonpathogenic, leaving
E. floccosum as the only species causing infections in humans.
24
The colonies of E. floccosum grow moderately rapidly and mature within 10 days.
Following incubation at 25 °C on potato dextrose agar, the colonies are brownish
yellow to olive gray or khaki from the front. From the reverse, they are orange to
brown with an occasional yellow border. The texture is flat and grainy initially and
become radially grooved and velvety by aging. The colonies quickly become downy
and sterile (Dehoog et al 2000; Larone, 1995; St Germain and Summerbell 1996;
Sutton et al 1998).
Septate, hyaline hyphae, macroconidia, and occasionally, chlamydoconidium-like cells
are seen. Microconidia are typically absent. Macroconidia (10-40 x 6-12 μm) are thin
walled, 3- to 5- celled, smooth, and clavate-shaped with rounded ends. They are
found singly or in clusters. Chlamydoconidium-like cells, as well as arthroconidia, are
common in older cultures (Dehoog et al 2000; Larone, 1995; St Germain and
Summerbell 1996; Sutton et al 1998). Epidermophyton floccosum is differentiated from
Microsporum and Trichophyton by the absence of microconidia.
25
Microscopic morphology of E. flocosum showing characteristic thin-walled
macroconidia in clusters. No microconidia are formed
Table 1.0 Characteristic of Some Commonly Isolated Dermatophytes
DERMATOPHYTES COLONIAL
MORPHOLOGY
GROWTH
RATE
MICROSCOPIC
IDENTIFICATION
Microsporum
audouinli
Downy white to
salmon Pink colony.
2 week
Sterile hypae: terminal
chlamydosporesm, favic
chandeliers, and
pectinate bodies;
macroconidia rarely
seen – bizarre shaped if
seen; micronodia rare or
absent
M. canis
Colony is usually
membranous with
feathery periphery;
centre of colony is
white to butt over
orange –yellow or
lemon yellow or
yellow orange apron
and reverse.
1 week
Thick walled, spindle
shaped, multiseptate,
rough walled,
macroconidia some with
macroconidia rarely
seen
26
Microsporum
gypscum
Cinnamon coloured,
powdery, colony
reverse light tan
1 week Thick-walled, rough,
elliptical, multisapate,
macroconidia,
microconidia few or
absent.
Epidermophyton
floccosum
Center of colony
tends to be folded
and is khaki green,
periphery is yellow;
reverse yellowish
brown with
observable folds
1 week Macroconidia large,
smooth-walled
multisepate, clavate anf
borne singly or in cluster
of two or three
microconidia not formed
by this species.
Trichophyton
mentagrophytes
Different colonial
types; white or
pinkish, granular and
fluffly varieties;
occasional light
yellow periphery in
younger cultures,
reverse buff to
reddish brown.
7-10
days
Many round to globose
microconidia most
commonly borne in
grapelike cluster or
laterally along the
hyphea; spiral hyphae in
30% of isolates,
macroconidia are thinwalled,
smooth, clubshaped,
and
multisepate, numerous
or are depending upon
strain.
Trichophyton
rubrum
Colonial types vary
from white dowry to
pink granular, rugal
folds are common,
reverse yellow when
colony is young
however, wine red
colour commonly
develop with age.
2 weeks Microconidia usually
teardrop, most
commonly borne along
sides of the hyphae,
macroconidia usually
absent, but when
present are smooth thin
walled and pencilshaped.
Trichophyton
tonsurans
White, tan to yellow
or rust, suedelike to
powdery; wrinkled
with heaped or
sunken center;
reverse yellow to tan
to rust red.
7-14
days
Microconidia are
teardrop or club shaped
with flat bottoms;vary in
size but usually larger
than other
dermatophytes;
macroconidia rare and
balloon forms found
when present
Trichophyton
schoenleinii
Irregularly heaped,
smooth white to
cream colony with
radiating grooves;
reverse white.
2-3
weeks
Hyphae usually sterile;
many antler-type hyphae
seen (favic chandeliers)
27
Trichophyton
violaceum
Port wine to deep
violet colony, may be
heaped or flat with
waxy-glabroussurface;
pigment may
be lost on subculture
2-3
weeks
Branched, tortuous
hyphae that are sterile;
chlamydospores
commonly aligned in
chains
Trichophyton
verrucosum
Glabrous to velvety
white colonies; rare
stains produce
yellow-brown colour;
rugal folds with
tendency to sink into
agar surface
2-3
weeks
Microconidia rare; large
and tear-drop when
seen; macroconidia
extremely rare, but
forms characteristic ‘rattail’
types when seen;
many chlamydospores
seen in chains,
particularly when colony
is incubated at 370 C
(Koneman and Roberts1985).
1.2 TINEA CAPITIS
Tinea capitis (scalp ringworm) is a highly contagious infection of the scalp and hair
caused by dermatophyte fungi such as M. canis, M. audounii. It occurs in all age
group but predominantly children. It is endemic in some of the poorest countries
(Gonzalez et al 2004).
1.2.1 PATHOPHYSIOLOGY OF TINEA CAPITIS
Tinea capitis is caused by species of Trichophyton and Microsporum. Tinea capitis is
the most common pediatric dermatophyte infection worldwide. It affects mostly
children of primary school age. The increased incidence of tinea among prepubertal
children has been attributed to reduced fungistatic properties of the child’s sebum.
However comparison studies of sebum in prepubertal versus postpubertal children
failed to reveal real fungistatic differences (Gorbach et al 1997).
28
Prepubertal infections by Trichophyton tonsurans, do not resolve at puberty, as do the
infections by Microsporum (Bronson et al 1983). Kamalam and Thambiah, (1980)
supposes that sebum is not of much value against the Trichophyton species.
1.2.2 EPIDEMIOLOGY OF TINEA CAPITIS
Tinea capitis, primarily a disease of children, (Aly 1999; Gupta and Summerbell 2000)
is a public health problem in some countries because of increased incidence and
epidemic transmission. Tinea capitis occur occasionally in other age groups. It is seen
most commonly in children younger than 10 years. Peak age range is in patients aged
3-7 years (Mandell et al 1995).
Tinea capitis affects boys more than girls probably because short hairs help
implantation of spores (Kanwar and Belhal, 1987). Although very rare after puberty,
when it occurs, it is often associated with the infection simultaneously at another site
(tinea corporis, tinea cruris, etc.), which is not so frequent in children (Kamalam and
Thambiah, 1980).
In adults it affects mostly women (Bronson et al 1983) and the area of choice is the
occiput. There is usually a trigger factor such as diabetes mellitus, pulmonary
tuberculosis, immunodefficiency, malnutrition, drugs or some other factor that causes
immunossupression (Kamalam and Thambiah, 1980). It is not infrequent in
transplanted patients or in those with systemic lupus erythematosus (Barlow and
Saxe, 1988).
Incidence of tinea capitis may vary by sex, depending on the causative fungal
organism. In M. audouinii–related tinea capitis, boys are affected much more
29
commonly. The infection rate has been reported to be up to 5 times higher in boys
than in girls; however, the reverse is true after puberty, possibly as a result of
increased exposure to infected children by women and to hormonal factors. In
infection by M. canis, the ratio varies, and the infection rate usually is higher in male
children. Girls and boys are affected equally by Trichophyton infections of the scalp,
but in adults, women are infected more frequently than are men.
The epidemiology of tinea capitis in the United Kingdom has recently changed
dramatically, (Higgins et al 2000) reflecting a similar trend in the United States 20
years ago (Bronson et al 1983). In the United Kingdom it is becoming a major public
health problem, and Afro-Caribbean children are particularly affected (Fuller et al
2003a). The predominant organism was M. canis, but now T. tonsurans causes 90%
of cases in the United Kingdom and the United States (Higgins et al 2000). T.
tonsurans is an anthropophilic fungus, which spreads from person to person. The
reason for this change is unclear, but hairdressing practices such as shaving the
scalp, plaiting, and using hair oils may increase the spread (Higgins et al 2000).
This variation in the epidemiology of tinea capitis reflects people’s habits, standards of
hygiene, climatic conditions and levels of education. Interestingly, increased education
may increase the number of patients seeking medical attention for their scalp lesions,
which in turn increase the diagnosed level of tinea capitis in a given area.
1.2.3 FREQUENCY OF TINEA CAPITIS
The frequency of tinea capitis compared to other types of dermatophytosis varies from
one location to another. Tinea capitis is considered the most frequent cause of
30
dermatophytosis in the Islamic Republic of Iran and Jordan (Chadegani,
1987,Khosravi et al 1994 Shtayeh and Arda 1985) and the second most frequent form
of dermatophytosis in Mosul (Iraq) after tinea corporis (Yehia, 1980). In contrast, there
has been a marked decline in the incidence of tinea capitis in Mexico City, down from
31.0% of all cases of dermatophytosis between 1940 and 1950 to 1.6% between 1986
and 1992 (Gayosso, 1994).
Tinea capitis is widespread in some urban areas in North America, Central America,
and South America. It is common in some parts of Africa and India. In Southeast Asia,
the rate of dermatophytic infection has been reported to decrease dramatically from
14% (average of male and female children) to 1.2% in the last 50 years because of
improved general sanitary conditions and personal hygiene. In northern Europe, the
disease is sporadic (Gupta et al 1999).
1.2.4 GEOGRAPHIC DISTRIBUTION OF TINEA CAPITIS
The geographic distribution and prevalence of dermatophytes are not static but
change under the influence of various forces such as climate, migration of people and
developments in prophylaxis and therapy.
T. tonsurans is now the major cause of tinea capitis in the USA (Matsuoka and Gedz,
1982; Rebell and Tschen 1984) but until some years ago it was M. canis and M.
audouinii (Matsuoka and Gedz 1982; Tschen, 1984). These fungi have been reported
to be the major cause of tinea capitis infection in Chicago over the past 20 years
(Bronson et al 1983). In New York, the predominantly infected children were reported
to be black (30 cases out of 31) (Ravits and Himmerstein, 1983) and in Philadelphia
since 1979 (Shockman and Urbach, 1983).
31
The incidence of the dermatophytes causing tinea capitis varies greatly. In Western
Australia, the major causative agent is M. canis (McAleer, 1980) as it is in Umbria,
Italy (Binazzi et al 1983) and Uruguay (Vignale et al 1983). In Madras, India, it is T.
violaceum (Kamalam and Thambiah 1980) while in Tel Aviv, Israel, T. schoenleinii is
the causative organism whereas in Ile-Ife, Nigeria, M. audouinii was found to be the
major causative organism (Ajao and Akintunde 1985). However, in South Africa, T.
violaceum was found to be the causative agents of Tinea capitis (Barlow and Saxe
1988).
Garcia-Perez & Moreno-Gimenez (1981), reviewing the literature on tinea capitis in
adults, found 39.59% of the cases caused by T. tonsurans. In Japan only a few cases
of T. tonsurans have been reported (Yamasaki et al 1982) and in Israel among 1000
cases of dermatophytosis not a single case of tinea capitis associated with T.
tonsurans as infective organism could be found.
Furtado et al (1985), in Manaus, State of Amazon, found among 115 cases of tinea
capitis, 91.7% was caused by T. tonsurans, out of these 91.7%, 13.9% were adults of
which 52.2% were women. In Rio de Janeiro, Brazil, some cases of tinea capitis in
adults due to M. canis and T. tonsurans have been reported (Severo and Gutierrez
1985; Miranda et al 1989).
1.2.5 CLINICAL MANIFESTATION OF TINEA CAPITIS
The clinical picture of tinea capitis varies greatly and depends mainly on the type of
infective agent. In general, zoophilic species produce much more severe inflammation
than those which are confined to humans (anthropophilic). In some cases, the
32
inflammation can be minimal with delicate scaling and inappreciable hair loss. In some
individuals an asymptomatic carrier state occurs.
Tinea capitis causes patchy alopecia, but specific clinical patterns can be varied. Six
main patterns are recognised as shown in Table 1.1
Table 1.1: Main clinical manifestation of tinea capitis according to occurrence.
Tinea capitis Clinical Patterns
Grey type Circular patches of alopecia with marked scaling
Moth eaten Patchy alopecia with generalised scale
Kerion Boggy tumour studded with pustules; lymphadenopathy usually present
Black dot Patches of alopecia with broken hairs stubs
Diffuse scale Widespread scaling giving dandruff-like appearance
Pustular type Alopecia with scattered pustules; lymphadenopathy usually present
(Fuller et al 2003b)
There are different types of Tinea capitis. The first type is the ringworm of the scalp
commonly associated with to M. audouni. Its hallmarks appear as patchy alopecia,
scaling, and dull broken hairs (“gray patch”). In another type of scalp involvement,
scattered individual hairs are affected. In children, the head is the most commonly
affected area, but lesions may occur on any place on the body. The primary lesion is
usually a small vesicle, although the most important characteristic of the lesion is lack
of inflammatory response. The lesions usually involve small area on the scalp in which
the hair is dull, and broken off about 1 to 2mm from the surface of the skin. The skin is
scaly with little inflammation. Lesions may occur around the nape of the neck and
occasionally the glabrous skin, and even the eyelids and eyelashes are involved.
33
A second type of tinea capitis is that caused by M.canis. The lesions are usually more
inflammatory from the beginning than those produced by M.audouni. There are usually
three to four small spots of the eruption in the scalp. The primary lesion is formed of
minute vesicles, and the hair is usually broken off 1 to 2 mm from the skin surface. At
times the hair may even be lost as a result of the inflammation around the hair follicle.
The centre of the lesion is elevated, and the borders of the lesions are more inflamed
than those seen with M. audouni. The vesicles are seen more readily around the
actively advancing margin of the lesion. The glabrous skin is frequently infected. This
form of the disease is frequently transmitted in young animals, such as kittens or
puppies, to man.
A third type of tinea infection of the scalp is the so-called kerion formation, otherwise
known as tinea profunda or the granulomatous disease of majocchi. This type of tinea
is very inflammatory and is caused by a virulent fungus of either animal or human
origin. The onset is rather acute, and the lesions usually remain localized to one spot.
The inflammatory reaction is rather severe. The lesion is boggy and indurated, and the
inflamed lesion is studded with broken or unbroken hairs, vesicles and pustules. The
organisms usually causing kerion formation are T. mentagrophytes, T. verrucosum, M.
canis, and M. gypseum.
A fourth type of tinea capitis is that produced by T. tonsurans and T. violaceum,
commonly known as “black dot” ringworm. It is characterized by multiple bald patches
on the scalp, with hairs broken at or below the surface of the scalp. Occasionally
folliculitis may be noted, and the patients may actually develop permanent baldness.
No fluorescence is noted. The organisms invade the hair, producing an endothrix type
34
of infection, causing the shafts of the shaft of the hair to break at or below the surface
of the skin. The disease may persist many years, causing some degree of atrophy of
the scalp, scarring and permanent alopecia.
1.2.6 DIAGNOSIS OF TINEA CAPITIS
Laboratory diagnosis of dermatophytosis depends on examination and culture of
rubbings, scrapings, pluckings, or clippings from infected lesions. Infected hairs
appearing as broken stubs are best for examination. They can be removed with
forceps without undue trauma or collected by gentle rubbing with a moist gauze pad or
toothbrush.
Selected hair samples are cultured or allowed to soften in 10-20% potassium
hydroxide (KOH) before examination under the microscope. Examination of KOH
preparations (KOH mount) usually determines the proper diagnosis if a tinea infection
exists.
Microscopic examination of the infected hairs may provide immediate confirmation of
the diagnosis of ringworm and establishes whether the fungus is small-spore or largespore
ectothrix or endothrix.
Culture provides precise identification of the species for epidemiologic purposes.
Primary isolation is carried out at room temperature, usually on Sabouraud dextrose
agar containing antibiotics (penicillin/streptomycin or choramphenicol) and
cycloheximide (Acti-dione), which is an antifungal agent that suppresses the growth of
environmental contaminant fungi. In cases of tender kerion, the agar plate can be
inoculated directly by pressing it gently against the lesion. Most dermatophytes can be
identified within 2 weeks, although T. verrucosum grows best at 37ºC and may have
35
formed only into small and granular colonies at this stage. Identification depends on
cultural characteristics, gross colony and microscopic morphology.
Infected hairs and some fungus cultures fluoresce in ultraviolet light. The black light
commonly is termed Wood lamp. Light is filtered through a Wood nickel oxide glass
(barium silicate with nickel oxide), which allows only the long ultraviolet rays to pass
(peak at 365 nm).
Hairs infected by M. canis, M. audouinii, and M. ferrugineum fluoresce a bright green
to yellow-green colour. Hairs infected by T. schoenleinii may show a dull green or
blue-white color, and hyphae regress leaving spaces within the hair shaft. T
verrucosum exhibits a green fluorescence in cow hairs, but infected human hairs do
not fluoresce .The fluorescent substance appears to be produced by the fungus only
in actively growing infected hairs.Infected hairs remain fluorescent for many years
after the arthroconidia have died. When a diagnosis of ringworm is under
consideration, the scalp is examined under a Wood lamp. If fluorescent infected hairs
are present, hairs are removed for light microscopic examination and culture.
Infections caused by Microsporum species fluoresce a typical green color. The myriad
debilitating effects of these manifested infective fungi necessitated the need for
effective therapeutic agents.
1.3 ANTIFUNGAL AGENT
An antifungal agent is a drug that selectively eliminates fungal pathogens from a host
with minimal or without toxicity to the host. The development of antifungal agents has
lagged behind that of antibacterial agents. This is a predictable consequence of the
cellular structure of the organisms involved. Bacteria are prokaryotic and hence offer
numerous structural and metabolic targets that differ from those of the human host.
36
Fungi, in contrast, are eukaryotes, and consequently most agents toxic to fungi are
also toxic to the host. Fungi generally grow slowly and often in multicellular forms so
they are more difficult to quantify than bacteria. This difficulty complicates experiments
designed to evaluate the in vitro or in vivo properties of a potential antifungal agent.
Despite these limitations, numerous advances have been made in developing new
antifungal agents and in understanding the existing ones.
There are different classes of antifungal agents and they include the following:
a) Polyene Antifungal Drugs
The polyene compounds are so named because of the alternating conjugated double
bonds that constitute a part of their macrolide ring structure. The polyene antibiotics
are all products of Streptomyces species. These drugs interact with sterols in cell
membranes (ergosterol in fungal cells; cholesterol in human cells) to form channels
through the membrane, causing the cells to become leaky. The polyene antifungal
agents include nystatin, amphotericin B, and pimaricin.
AMPHOTERICIN B
Amphotericin B is a polyene antifungal agent, first isolated from Streptomyces
nodosus in 1955. It is an amphoteric compound composed of a hydrophilic
polyhydroxyl chain along one side and a lipophilic polyene hydrocarbon chain on the
other. Amphotericin B is poorly soluble in water (Terrell and Hughes 1992).
37
Amphotericin B binds to sterols, preferentially to the primary fungal cell membrane
sterol, ergosterol. This binding disrupts osmotic integrity of the fungal membrane,
resulting in leakage of intracellular potassium, magnesium, sugars, and metabolites
and then cellular death (Terrell and Hughes, 1992).
Amphotericin B has a very broad range of activity and is active against most
pathogenic fungi e.g Coccidioides immitis, Histoplasma capsulatum, Blastomyces
dermatitidis and Paracoccidioides brasiliensis. Notable exceptions include
Trichosporon beigelii (Walsh et al, 1990), Aspergillus terreus (Sutton et al 1999),
Pseudallescheria boydii (Walsh et al, 1992), Malassezia furfur (Francis and Walsh,
1992), and Fusarium spp (Arikan et al ,1999). Among the Candida spp, isolates of C.
albicans, C. guilliermondii, C. lipolytica, C. lusitaniae C. norvegensis C. tropicalis C.
glabrata, and C.krusei have been reported to be relatively resistant to amphotericin B
(Karyotakis and Anaissie, 1994; Karyotakis et al, 1993; Meyer, 1992 and Terrell and
Hughes, 1992). Reduced susceptibility has been observed specifically at fungicidal
levels for C. parapsilosis.
38
The most commonly observed infusion-related side effects of amphotericin B
deoxycholate are fever, chills, and myalgia. These can be partially overcome by
premedication with diphenhydramine and/or acetaminophen (Goodwin et al 1995).
Nephrotoxicity is the major adverse effect limiting the use of amphotericin B. The
manifestations of nephrotoxicity are azotemia, decreased glomerular filtration, loss of
urinary concentrating ability, renal loss of sodium and potassium, and renal tubular
acidosis (Meyer 1992). The renal injury reduces erythropoietin production and leads to
a normochromic normocytic anemia (Lin et al, 1990). Thrombophlebitis may occur at
the site of infusion. Thrombocytopenia may rarely be observed (Chan et al 1982).
b) Azole Antifungal Drugs
The azole antifungal agents have five-membered organic rings that contain either two
or three nitrogen molecules (the imidazoles and the triazoles respectively). The
clinically useful imidazoles are clotrimazole, miconazole, and ketoconazole. Two
important triazoles are itraconazole and fluconazole. The azoles inhibit fungal
cytochrome P450 3A-dependent C14- -demethylase that is responsible for the
conversion of lanosterol to ergosterol. This leads to the depletion of ergosterol in the
fungal cell membrane. The in-vitro antifungal activity of the azoles varies with each
compound, and the clinical efficacy of each compound may not coincide exactly with
in-vitro activity. The azoles are primarily active against C. albicans, C. neoformans, C.
immitis, H. capsulatum, B. dermatitidis, P. brasiliensis; C. glabrata, Aspergillus spp.,
and Fusarium spp. and zygomycetes are resistant to currently available azoles.
39
KETOCONAZOLE
Ketoconazole is an imidazole antifungal agent. It has five-membered ring structures
containing two nitrogen atoms. Ketoconazole is the only member of the imidazole
class that is currently used for treatment of systemic infections.
Ketoconazole is a highly lipophilic compound. This property leads to high
concentrations of ketoconazole in fatty tissues and purulent exudates. Expectedly, the
distribution of ketoconazole into cerebrospinal fluid is poor even in the presence of
inflammation. Its oral absorption and solubility is optimal at acidic gastric pH (Sheehan
et al, 1999; Van der Merr et al, 1980).
As with all azole antifungal agents, ketoconazole works principally by inhibition of
cytochrome P450 14a-demethylase (P45014DM). This enzyme is in the sterol
biosynthesis pathway that leads from lanosterol to ergosterol (Lyman and Walsh,
1992). The affinity of ketoconazole for fungal cell membranes is less compared to that
of fluconazole an itraconazole. Ketoconazole has thus more potential to effect
mammalian cell membranes and induce toxicity (Como and Dismukes, 1994).
40
Ketoconazole is active against Candida spp and Cryptococcus neoformans However,
its activity is limited compared to that of fluconazole and itraconazole Furthermore,
due to its limited penetration to cerebrospinal fluid, it is clinically ineffective in
meningeal cryptococcosis. Its activity against the dimorphic moulds, Histoplasma
capsulatum, Blatomyces dermatitidis, Coccidioides immitis, Sporothrix schenckii,
Paracoccidioides brasilliensis, and Penicillium marneffei is favourable. However,
fluconazole and itraconazole are at least as effective as ketoconazole against these
fungi and are safer. Thus, ketoconazole remains as an alternative second-line drug for
treatment of infections due to dimorphic fungi. Ketoconazole is not recommended for
treatment of meningeal infections due to Histoplasma capsulatum, Blastomyces
dermatitidis, and Coccidioides immitis due to its limited penetration to cerebrospinal
fluid (Como and Dismukes, 1994).
Ketoconazole is also active against Pseudallescheria boydii and is a good alternative
for treatment of pseudallescheriasis (Sheehan et al, 1999). It is also effective in
Pityriasis versicolor (Degreef and DeDoncker, 1994). Ketoconazole has practically no
activity against Aspergillus spp, Fusarium spp, and zygomycetes order of fungi (Como
and Dismukes, 1994).
The major drawbacks of ketoconazole therapy are from the occasionally seen adverse
reactions. It may induce anorexia, nausea and vomiting (Como and Dismukes, 1994;
Dismukes et al, 1983). Increase in transaminase levels and hepatoxicity may occur
(Lewis et al 1984; Walsh et al, 1991). Ketoconazole may decrease testosterone and
cortisol levels, resulting in gynecomastia and oligospermia in men and menstrual
41
irregularities in women (O’connor et al, 2002; Thomson and Carter, 1993).
FLUCONAZOLE
Fluconazole is a widely used bis-triazole antifungal agent. It has five-membered ring
structures containing three nitrogen atoms.
Fluconazole works principally by inhibition of cytochrome P450 14a-demethylase
(P45014DM). This enzyme is in the sterol biosynthesis pathway that leads from
lanosterol to ergosterol (Lyman and Walsh, 1992; Marriot and Richardson, 1987; Odds
et al ,1986).
Fluconazole is generally considered a fungistatic agent. It is principally active against
Candida spp. and Cryptococcus spp. However, Candida krusei is intrinsically resistant
to fluconazole. In addition, isolates of Candida glabrata often generate considerably
high fluconazole MICs, with as many as 15% of isolates being completely resistant
(Pfaller et al, 1999). Acquired resistance to fluconazole among Candida albicans
strains has been reported particularly in HIV-infected patients (Bodey, 1992; Colin et
al, 1999; Hoban et al, 1999; Rex et al, 1995).
42
Fluconazole has useful activity against Coccidioides immitis and is often used to
suppress the meningitis produced by that fungus (Galgiani, 1993). It has limited
activity against Histoplasma capsulatum (Wheat et al, 1997), Blastomyces dermatitidis
(Pappas et al, 1997), and Sporothrix schenckii (Kauffman et al, 1996), and is
sometimes used a second-line agent in these diseases. Fluconazole has no
meaningful activity against Aspergillus spp. or most other mould fungi (Bodey, 1992;
Denning et al 1992).
Carrillo-munoz et al (2003) studied the in vitro antifungal activity of sertaconazole
against 114 dermatophytes with low susceptibility to fluconazole following the National
Committee for Clinical Laboratory Standards for filamentous fungi (M38-P). However,
several important factors such as the temperature (28 vs. 35°C) and time of incubation
(4-10 days vs. 21-74 h), have been found to affect dermatophytes. Sertaconazole was
active against 114 isolates of 12 fungal dermatophyte species, showing an overall
geometric mean of 0.41 μg/ml with a minimum inhibitory concentration (MIC) range of
0.01-2 μg/ml against these isolates with reduced fluconazole susceptibility.
Differences between both antifungals were significant (p < 0.05). MIC50 and MIC90 of
sertaconazole were of 0.5 and 1 μg/ml, respectively, while the MIC of fluconazole was
16 μg/ml
For the in vitro susceptibility tests of fluconazole against some strains of Cryptococcus
neoformans the MIC ranges changed from 0.5-16 μg/ml in RPMI 1640 medium and
from 0.25 to 16 mg/ml in YNB-1 (Aves et al, 2002). Fluconazole has been shown to be
43
an effective alternative to amphotericin B in the treatment of cryptococcal meningitis
and is the most commonly used antifungal agent in maintenance therapy of this
disease (Powderly, 2000). The C. neoformans susceptibility to fluconazole could be an
important predictor of treatment success and MICs can be useful to monitor possible
development of resistance during therapy and to identify primary resistance (Amengou
et al, 1996; Coker et al, 1991; Espinel-Ingroff et al, 1997; Orni-Wasserlauf et al, 1999;
Paugam et al, 1994; Peetemans et al, 1993; Witt et al, 1996).
Fluconazole has been found to have MIC of 256–512 mg/L against isolates of A.
fumigatus A. terreus and A. flavus which fell to 16–128 mg/L when combined with
terbinafine (Mosquera et al 2002).
Fluconazole is generally quite well tolerated. In common with all azole antifungal
agents, fluconazole may cause hepatotoxicity. Fluconazole has both oral and
intravenous formulations. Fluconazole is a very widely used antifungal agent. It is one
of the first-line drugs, particularly in treatment of infections due to Candida spp. other
than Candida krusei and some Candida glabrata isolates. Fluconazole is commonly
used also for prophylaxis in transplant patients (Patel, 2000; Wolff et al 2000).
44
C) 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.
TERBINAFINE
Terbinafine is an allylamine structurally related to naftifine. It is a synthetic antifungal
agent. It is highly lipophilic in nature and tends to accumulate in skin, nails, and fatty
tissues (Elewski, 1998; Roberts, 1994).
Terbinafine inhibits ergosterol biosynthesis via inhibition of squalene epoxidase. This
enzyme plays a vital role in the fungal sterol synthesis pathway that enhances the
production of sterols needed for functional fungal cell membrane.
Terbinafine is mainly effective on a specific group of fungi such as dermatophytes.
The in-vitro activity of terbinafine has been tested against various dermatophytes.
45
Terbinafine yields lower MICs compared to fluconazole, itraconazole and griseofulvin
(Jessup et al, 2000b), an indication of likely better performance.
Terbinafine has better in-vitro activity also against most Candida spp, Aspergillus spp,
Sporothrix schenckii (Jessup et al, 2000a), Penicillium marneffei (McGinnis et al,
2000), Malassezia furfur (Petranyi et al, 1987), Cryptococcus neoformans (Ryder et al,
1998), Trichophyton spp. and Blastoschizomyces (Ryder, 1999).
The in-vitro antifungal susceptibilities of six clinical Trichophyton rubrum isolates
obtained sequentially from a single onychomycosis patient who failed oral terbinafine
therapy (250 mg/day for 24 weeks) were determined by broth microdilution and
macrodilution methodologies (Mukherjee et al, 2003).
The MICs of terbinafine for these resistant strains were >4 μg/ml, whereas they were
<0.0002 μg/ml for the susceptible reference strains. Consistent with these findings, the
minimum fungicidal concentrations (MFCs) of terbinafine for all six strains were >128
μg/ml, whereas they were 0.0002 μg/ml for the reference susceptible strains. The MIC
of terbinafine for the baseline strain (cultured at the initial screening visit and before
therapy was started) was already 4,000-fold higher than normal, suggesting that this is
a case of primary resistance to terbinafine. The results obtained by the broth
macrodilution procedure revealed that the terbinafine MICs and MFCs for sequential
isolates apparently increased during the course of therapy. RAPD analyses did not
reveal any differences between the isolates. The terbinafine-resistant isolates
exhibited normal susceptibilities to clinically available antimycotics including
itraconazole, fluconazole, and griseofulvin (Mukherjee et al, 2003).
46
Soares and Curry (2001) evaluated the in vitro activity of antifungal and antiseptic
agents against dermatophytes isolated from patients with tinea pedis. The spore
population per ml used was 106 cells/ml. The MICs of terbinafine for the strains were
0.007μg/ml or 0.015μg/ml. Most strains of T. rubrum (16; 72.7%), T. mentagrophytes
(24; 72.7%) and E. floccosum (2; 50%) were inhibited at concentration of 0.007μg/ml.
The MFC ranged from0.03 μg/ml to > 4 μg/ml. This antifungal agent was lethal to two
strains of E. floccosum at the concentration of 0.03μg/ml, and at 0.5 μg/ml it was lethal
to the other two strains. The fungicidal concentration for 13 (59.1%) strains of T.
rubrum was up to 0.25 μg/ml, and for 20 (60.6%) strains of T. mentagrophytes it was
up to 0.5 μg/ml. Only 2 and 6 strains of T.rubrum and T. mentagrophytes, respectively,
were not killed by concentrations up to 4 μg/ml
In order to develop new approaches for the chemotherapy of invasive infections
caused by Scedosporium prolificans, the in-vitro interaction between itraconazole and
terbinafine against 20 clinical isolates was studied using a checkerboard microdilution
method. Itraconazole and terbinafine alone were inactive against most isolates, but
the combination was synergistic against 95 and 85% of isolates after 48 and 72 h of
incubation, respectively. Antagonism was not observed. The MICs obtained with the
terbinafine-itraconazole combination were within levels that can be achieved in
plasma. (Meletiadis et al, 2000).
The MICs of terbinafine and itraconazole based on 50% reduction of growth for P.
variotii were 0.125 and 0.25 μg/ml, respectively. Itraconazole was inactive in vitro
47
against most isolates, with the MIC at which 90% of the isolates were inhibited being
>32 μg/ml after both 48 and 72 h of incubation. An attempt was made to establish the
exact MIC of itraconazole by an agar dilution method. Serial dilutions ranging from 32
to 512 μg of itraconazole per ml were made in RPMI 1640 agar. The growth of none of
the S. prolificans isolates was inhibited by any of these concentrations after 48 h of
incubation. Therefore, a MIC of 64 μg/ml was chosen for calculations for those isolates
that grew in the wells that contained the highest concentration of itraconazole. The
MIC of terbinafine at which 90% of the isolates were inhibited was 2 μg/ml after 48 h
but increased to 64 μg/ml after 72 h. Synergism was found for 19 of 20 (95%) of the S.
prolificans isolates after 48 h and for 17 of 20 (85%) of the isolates after 72 h of
incubation. For three isolates the effect of the combination appeared to be indifferent
after 72 h of incubation, and antagonism was not observed (Meletiadis et al, 2000).
Mock et al (1998) studied the sensitivity of different species of dermatophytes towards
terbinafine and itraconazole, and compared the results with a retrospective study on
35 immunocompetent patients with tinea capitis who were treated with terbinafine
(Lamisil®). Each tested species of dermatophyte was sensitive to terbinafine and
itraconazole at different concentration ranges. The MIC for terbinafine ranged from
0.005 to 0.5 μg/ml and for itraconazole from 40 to 80 μg/ml. Microsporum canis was
the dermatophyte least sensitive to terbinafine. The study showed that the cure rate
was excellent for Trichophyton violaceum and T. soudanense, variable for T.
mentagrophytes and poor for M. canis and M. langeronii.
Adverse reactions to terbinafine are in general transient and mild. The incidence of
48
these reactions has been found to be 10.5% in a large scale study. These adverse
reactions are mostly with gastrointestinal system and the skin (Hall et al, 1997).
Reversible agranulocytosis has been reported as a rare side effect (Ornsteins and Ely,
1998).
Terbinafine is one of the mainstays of treatment of dermatophytosis. Compared to the
previously existing antifungal agent, griseofulvin, it is more effective, as well as being
significantly less toxic. Moreover, the required duration of therapy is also shorter with
terbinafine.
This property is of interest, particularly in cases of onychomycosis where prolonged
courses of therapy are needed (Arenas et al, 1995). Terbinafine is a safe and
efficacious agent in treatment of onychomycosis (Drake et al, 1997; Hecker, 1997), as
well as other dermatophytosis. It appears to be similarly or more effective than its
alternative, itraconazole and fluconazole (DeBacker et al, 1998; Roberts, 1994; Havu
et al, 2000).
Terbinafine, when combined with fluconazole, has occasionally been successful in
treatment of oropharyngeal infections due to fluconazole-resistant Candida spp.
(Ghannoun and Elewski, 1999). A report has suggested a possible role for terbinafine
as drug of choice against azole-resistant oropharyngeal infections (Vazquez et al,
2000)
49
d) Antimetabolite Drugs
5-Fluorocytosine acts as an inhibitor of both DNA and RNA synthesis via the
intracytoplasmic conversion of 5-fluorocytosine to 5-fluorouracil.
FLUCYTOSINE
Flucytosine (5-fluorocytosine; 5-FC; 4-amino-5-fluoro-2-pyrimidone) is an
antimetabolite type of antifungal drug. It is chemically a pyrimidine. It is activated by
deamination within the fungal cells to 5-fluorouracil.
Flucytosine is the the only available antimetabolite drug having antifungal activity. It
inhibits fungal protein synthesis by replacing uracil with 5-flurouracil in fungal RNA.
Flucytosine also inhibits thymidylate synthetase via 5-fluorodeoxy-uridine
monophosphate and thus interferes with fungal DNA synthesis. Flucytosine is active
against Candida spp, Cryptococcus neoformans, Aspergillus spp. and the
50
dematiaceous fungi, Phialophora spp and Cladosporium spp. causing
chromoblastomycosis.
While flucytosine is in clinical use for few specific indications, its use alone in
treatment frequently results in emergence of resistance. This resistance has been
ascribed to mutations in cytosine permease or cytosine deaminase enzymes. Thus,
flucytosine is always administered with amphotericin B (Dismukes et al, 1983) or
fluconazole (Mayanja-Kizza et al, 1998) or with both amphotericin B and fluconazole
together (Diamond et al, 1998; Just-Nubling et al, 1996) as combination therapy.
Amphotericin B and flucytosine combination has proven to be favorable in treatment of
cryptococcal meningitis (Dismukes et al, 1987). Primary resistance to flucytosine by
Candida strains has also been speculated as a possibility (Barchiesi et al, 2000).
The adverse side effects of flucytosine has been reported to include gastrointestinal
intolerance and bone marrow depression. Rash, hepatotoxicity, headache, confusion,
hallucinations, sedation and euphoria have also been observed
Since flucytosine is commonly combined with amphotericin B, the renal impairment
caused by amphotericin B has been speculated to probably increase the flucytosine
levels in the body and thus potentiate its toxicity. The increase in toxicity of flucytosine
is presumably ascribed to 5-fluorouracil produced from flucytosine released by
bacteria in gut lumen.

 

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