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Mycopathologia (2008) 166:353–367

DOI 10.1007/s11046-008-9109-0

Update in Antifungal Therapy of Dermatophytosis


Aditya K. Gupta Æ Elizabeth A. Cooper

Received: 15 October 2007 / Accepted: 30 January 2008 / Published online: 14 May 2008
 Springer Science+Business Media B.V. 2008

Abstract Treatment of dermatophyte infection Introduction


involves primarily oral and/or topical formulations
of azoles or allylamines, particularly itraconazole and Dermatophyte organisms infect humans across the
terbinafine. Topical medications applied once or world, with widely varying frequency and epidemi-
twice daily are the primary treatment indicated for ology. Nonetheless, treatment methods are similar
tinea corporis/cruris, and tinea pedis/manuum. Use of across the world, and modern antifungal medications
oral antifungals may be practical where the tinea can provide effective treatment for most presenta-
involvement is extensive or chronic, or where appli- tions of dermatophytosis.
cation of a topical is not feasible. For tinea unguium There are few new medications available for
(onychomycosis) and tinea capitis, oral therapies are dermatophyte infection. Most agents, even where
the primary treatments provided. Recently, topical new, remain within the two main antifungal drug
amorolfine and ciclopirox formulations have been families, the azoles and the allylamines; a newer
approved for use in milder onychomycosis cases, and class, the echinocandins, is currently used only for
their role in the treatment of the different clinical systemic Candida/Aspergillus infection [1, 2]. Inno-
forms of onychomycosis is currently being defined. vation in dermatophyte treatment has involved
Relapse of infection remains a problem, particularly marketing of wide-spectrum topical agents, use of
with tinea pedis/unguium. Appropriate follow-up topical agents with anti-inflammatory as well as
duration and education of patients on proper foot antifungal actions, and use of a combination of
hygiene are also important components in providing existing oral antifungal agents, or oral/topical anti-
effective therapy. fungal agents, in attempts to improve on
monotherapy cure rates.
A. K. Gupta Current country-specific prescribing information
Division of Dermatology, Department of Medicine, for any antifungal should be consulted prior to
Sunnybrook Health Sciences Center, Toronto, ON, providing any medication. The information provided
Canada in this article may not reflect country-specific prac-
A. K. Gupta tices, due to the variation in antifungal formulations
University of Toronto, Toronto, ON, Canada and availability outside of North America. Regarding
the variety of topical antifungals available, this article
A. K. Gupta (&)  E. A. Cooper provides a general picture of topical antifungal
Mediprobe Research Incorporated, 645 Windermere
Road, London, ON, Canada N5X 2P1 treatment using topical medications most frequently
e-mail: agupta@execulink.com cited in medical literature, and does not attempt to

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354 Mycopathologia (2008) 166:353–367

provide a comprehensive listing of all topical formulations of itraconazole and terbinafine are the
antifungals available. most common drugs used for onychomycosis. Gris-
eofulvin plays a large role in tinea capitis treatment,
though its use has been superseded in other areas by
Topical Antifungal Medications itraconazole and terbinafine. The main pharmaco-
logical and safety properties of the oral agents are
Topical medications applied once or twice daily are listed in Table 2.
the primary treatment indicated for tinea corporis/ The oral antifungal medications may be associated
tinea cruris, and tinea pedis/tinea manuum (Table 1). with some potential for severe hepatic toxicity, rare
A wide variety of topical agents are available, in serious skin events such as Stevens–Johnson syn-
cream, gel, lotion, and shampoo formulations [3–10]. drome, and possible drug–drug interactions due to
A majority of the agents are of the ‘azole’ antifungal metabolism through the cytochrome P-450 system
family (clotrimazole, miconazole, econazole, oxicon- [12–17]. Current country-specific prescribing infor-
azole, tioconazole, …). Terbinafine and naftifine mation for any oral antifungal medication should be
represent the ‘allylamine’ family of agents. Both consulted prior to providing any medication.
families of drugs are known for their high efficacy Though oral antifungals are typically not approved
against the dermatophytes. In addition, amorolfine for use in children, pediatric use has been docu-
and butenafine are popular antifungals classed as mented widely in the medical literature for numerous
morpholine derivatives. Cure rates of tinea corporis/ indications, and has typically provided safety profiles
tinea cruris/tinea pedis are high, with infections similar to use in adults [18–20]. Oral suspensions are
resolving with 2–4 weeks of topical therapy. Safety available for many of the oral antifungals, providing
of therapy is less of a concern for topical medications easier dosing for children; however, the pharmaco-
than oral medications, as serum absorption tends to logical profiles of oral suspensions may differ from
be minimal with topical dermatophytosis therapy. capsule/tablet dosage.
Most adverse events following topical drug applica- Oral terbinafine is indicated for the treatment of
tion are skin reactions at the application site, which adults with dermatophyte onychomycosis of the
are mild and transient [11]. toenails and/or fingernails. Serum transaminase tests,
Bacterial superinfection may be present in some i.e., alanine transaminase (ALT) and aspartate trans-
cases of dermatophytosis, particularly in tinea pedis, aminase (AST) are suggested prior to beginning oral
thus a topical antifungal agent providing both anti- terbinafine and periodically during therapy, as there is
bacterial and antifungal activity may be desired, and some potential for liver dysfunction/damage with
many available agents have wide-spectrum effect. terbinafine use [12]. Terbinafine is not recommended
Similarly, inflammation is a component of some for patients with existing liver disease [12, 21].
dermatophytoses, and there are several topical anti- Terbinafine has been reported infrequently to precip-
fungal agents, which provide anti-inflammatory itate or exacerbate cutaneous and systemic lupus
action as well as effective antifungal therapy. erythematosus, and should be discontinued in patients
showing signs of lupus erythematosus; furthermore,
physicians should consider monitoring complete
Systemic Antifungal Medications blood counts in patients with known or suspected
immunodeficiency who are administered oral terbi-
For tinea unguium (onychomycosis) and tinea nafine for longer than 6 weeks [12]. Terbinafine is
capitis, oral therapies are the primary treatments metabolized through the CYP2D6 enzymes, and thus
provided, though there is evidence to suggest may interfere with other CYP2D6 drugs. Other drug
topicals can be effective in less-severe grades of interactions are possible, and a current country-
onychomycosis infection and two topical agents, specific product monograph should be consulted for
ciclopirox and amorolfine, have been approved for complete listing of known drug interactions, warn-
onychomycosis therapy (Table 1). Five main sys- ings and monitoring requirements prior to
temic agents are available: terbinafine, itraconazole, prescribing. Terbinafine may be taken in fasted or
fluconazole, griseofulvin, and ketoconazole. Oral fed state without affecting absorption.

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Table 1 Treatment options available for dermatophytoses
Terbinafine Itraconazole Fluconazole Ketaconazole Griseofulvin Topicals

Tinea pedis/ Creamb: apply twice Oral: 200 mg Oral: 150 mg once 2% Creamb: apply Microsizeb Ciclopiroxb Clotrimazoleb
manuuma daily 9 1–4 weeks bid for 1 week weekly for once daily for 1 g/day 0.77% Miconazoleb
b 2–6 weeks 6 weeks cream and
1% Solution : apply Ultramicrosize 660 Butenafineb
twice daily for Oralb: 200–400 or 750 mg/day gel twice
daily for Econazoleb
1 week mg/day for [4 for 4–8 weeks
weeks 4 weeks Naftifineb
Mycopathologia (2008) 166:353–367

Oral: 250 mg/day


2 weeks Antifungal Oxiconazoleb
powder for
prevention
Tinea corporis/ Creamb: apply twice Oral: 200 mg/day Oral: 150–300 mg 2% Creamb: apply Microsizeb Ciclopiroxb Clotrimazoleb
cruris daily 9 1–4 weeks for 1 week once weekly for once daily for 500 mg/day 0.77% Miconazoleb
b 2–4 weeks 2 weeks cream and
1% Solution : apply Ultramicrosize Butenafineb
twice daily for Oralb: 200–400 mg/ 330–375 mg/day gel twice
daily for 4 Econazoleb
1 week day for 4 weeks for 2–4 weeks
Naftifineb
Oral: 250 mg/day for
2–4 weeks Oxiconazoleb
Tinea capitis See Table 3: Pediatric See Table 3: See Table 3: Pediatric Only effective against See Table 3: Selenium Corticosteroid
dosing Pediatric dosing dosing Trichophyton Pediatric Dosing sulfide adjunct
2% shampoo used as shampoo therapy for
adjunct therapy 1% as severe
adjunct inflammatory
therapy varieties
Onychomycosis Oral: 250 mg/day Oral: Pulse therapy: Oral: 150 or 300 mg Oral: 200–400 mg/Microfine preparation: Amorolfine Ciclopiroxb 8%
Toenail: 12–16 weeks 200 mg bid for once weekly for day 9 6 months 500 mg daily 5% lacquer lacquer once
1 week, followed 6–12 months Not recommended due for 6–12 months daily for
Fingernail: 6 weeks
by 3 itraconazole- (Toenail: approx. to hepatotoxicity (FDA approved: 48 weeks
free weeks 9–15 months; risk Microsize 1 g/day
Toenails: 3 pulses Fingernail: Ultramicrosize 660
Fingernails only: approx. 4–9 months) or 750 mg/day
2 pulses for 4–12 months)
a
There are no approved treatments specifically for tinea manuum; treatments shown are for tinea pedis which are effective in the treatment of tinea manuum
b
FDA approved indication
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Table 2 Summary of systemic antifungal agent properties


Terbinafine [12] Itraconazole [13] Fluconazole [14] Griseofulvin [15, 16] Ketoconazole [17]

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Chemistry Allylamine Triazole Bis-triazole Spiro-benzo[b]furan Imidazole
Available as tablet Available as capsule, oral Available as tablet, oral Available as tablet or oral Available as tablet
Inhibits squalene solution or IV formulation suspension or IV formulation suspension Inhibition of C14 demethylation
epoxidase = ergosterol Inhibits fungal lanosterol Inhibits fungal lanosterol 14-aDisruption of fungal cell mitotic of cell membrane sterols (e.g.
deficiency (fungistatic) and 14-a demethlyase = ergosterol demethylase = ergosterol spindle, arresting cell division lanosterol); fungistatic;
accumulation of squalene deficiency (fungistatic) deficiency (fungistatic) (fungistatic) Concentrated in fungicidal at high
(fungicidal) Lipophilic; binds strongly More hydrophilic than other azoles skin, hair, nails, liver, fat and concentrations;
Lipophilic; Binds strongly to plasma proteins ([99%) skeletal muscles; deposited in 84–99% bound to plasma
Protein binding of 11–12% keratin precursor cells, and proteins
([99%) and nonspecifically Extensively metabolized in the
to plasma proteins No significant first-pass bound to new keratin Partially metabolized in liver
liver predominantly by CYP3A4 hepatic metabolism
Extensively metabolized in Oxidative demethylation
liver principally in liver
Metabolism Reported to inhibit CYP 2D6 Potential for itraconazole Potent inhibitor of CYP2C9, Induces hepatic enzymes— May inhibit synthesis of
in vitro: use with caution in metabolism alteration where and CYP2C19; weaker potential for adverse events, adrenal steroids, testosterone
patients with concomitant 2D6 CYP3A4 is altered by other inhibition of CYP3A drug interactions Potent inhibitor of CYP3A
substrates such as tricyclic medications group—potential for drug group—possible drug
antidepressants interactions interactions
Contraindications None Patients with evidence of Severe liver disease; Use with Patients with porphyria or Cisapride
ventricular dysfunction such as caution in patients sensitive hepatocellular failure Triazolam
congestive heart failure (CHF) or to other azoles
a history of CHF; Cisapride, Terfenadine, Astemizole
Cisapride
Midazolam (oral), Triazolam,
Terfenadine, Astemizole, Terfenadine
Pimozide, Quinidine, Dofetilide,
Levacetylmethadol
(levamethadyl) HMG CoA-
reductase inhibitors: lovastatin,
simvastatin, ...; Ergot alkaloids
metabolized by CYP3A4:
dihydroergotamine, ergometrine
(ergonovine), ergotamine,
methlergometrine
(methylergovovine)
Cautions Monitor CYP2D6-metabolized Use is strongly discouraged for Discontinue in patients Use with caution in patients with Close monitoring of hepatic
drug concentration for patients with elevated or showing signs/symptoms penicillin sensitivity function required;
increases (tricyclic abnormal liver enzymes or active of liver disease Female patients should be aware Discontinue in patients
antidepressants, selective liver disease, or who have Use with caution in patients that there is a possibility of showing signs/symptoms of
serotonin reuptake inhibitors, experienced liver with potential proarrhythmic decreased oral contraceptive liver disease
beta-blockers and monoamine toxicity with other drugs conditions efficacy with griseofulvin use Recommended dosage should
oxidase inhibitors type B) be followed closely to avoid
depression of adrenocortical
function and serum
testosterone
Mycopathologia (2008) 166:353–367
Table 2 continued
Terbinafine [12] Itraconazole [13] Fluconazole [14] Griseofulvin [15, 16] Ketoconazole [17]

Not recommended for patients with Baseline LFTs for all patients; Monitor patients developing rashes Patients using oral
chronic or active liver disease; Discontinue in patients showing closely for signs of exfoliative hypoglycemics should
baseline LFTs for all patients signs/symptoms of liver disease skin disorders closely monitor blood sugar;
Not recommended for Use with caution in patients Patients using oral hypoglycemics may need to adjust
patients with renal impairment sensitive to other azoles should closely monitor blood hypoglycemic dosing
(creatinine clearance Advise patients with risk factors sugar; may need to adjust
B50 ml/min) for CHF (ischemic and valvular hypoglycemic dosing
Discontinue in patients with disease, significant pulmonary
clinical signs or symptoms disease, renal failure or other
of lupus erythematosus edematous disorders) to watch
Mycopathologia (2008) 166:353–367

Monitor complete blood counts for signs and symptoms of CHF


in patients with known or Discontinue if signs of neuropathy
suspected immunodeficiencies develop
(terbinafine used [6 weeks), Patients using oral hypoglycemics
for decrease in lymphocyte should closely monitor blood
counts, neutrophil counts sugar; may need to adjust
hypoglycemic dosing
Drug (capsules) should be taken
after a full meal or with an 8oz
cola beverage
Adverse events GI: Diarrhea (5.6%), dyspepsia GI: Diarrhea (4%), dyspepsia (4%), GI: Nausea (3.7%), vomiting GI: Epigastric distress; nausea, GI: Nausea and/or vomiting
(4.3%), nausea (2.6%), flatulence (4%), abdominal pain (1.7%), abdominal pain (1.7%), vomiting, excessive thirst; (3–10%); 1% or less of
abdominal pain (2.4%), (4%), nausea (3%), appetite diarrhea (1.5%) flatulence; diarrhea; oral thrush patients: Abdominal pain,
flatulence (2.2%), taste increase (2%), constipation Cutaneous: Skin rash (1.8%) Cutaneous: Hypersensitivity constipation flatulence, GI
disturbance (2.8%) Cutaneous: (2%), gastritis (2%), reactions including rash, and bleeding, diarrhea
Rash (5.6%), pruritis (2.8%), gastroenteritis (2%) urticaria CNS: Headache, Cutaneous: Pruritis (2%)
urticaria (1.1%) CNS: Headache Cutaneous: Rash (4%) fatigue, dizziness, insomnia
(12.9%) Hepatic/Renal: Liver Less than 1%: Rash, dermatitis,
enzyme abnormalities (C29 purpura, urticaria
upper limit of normal) (3.3%)
Other: Visual disturbance (1.1%)
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Table 2 continued
358

Terbinafine [12] Itraconazole [13] Fluconazole [14] Griseofulvin [15, 16] Ketoconazole [17]

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Rare events based on worldwide CNS: Headache (10%), dizziness CNS: Headache (1.9%) Post-marketing experiences (rare): CNS: Less than 1%: Headache,
experience with terbinafine (4%), abnormal dreaming (2%) Post-marketing experiences (rare): Paresthesia of hands and feet; dizziness, somnolence,
tablets: Hepatic/Renal: Liver function Mental confusion, impairment lethargy, asthenia,
Rare cases of serious hepatic of performance of routine nervousness, insomnia,
Idiosyncratic and symptomatic abnormality (3%), liver enzyme reactions ranging from mild
hepatic injury and cases of liver abnormalities (C2x upper limit activities and psychotic abnormal dreaming,
transient elevations in symptoms with large doses; GI photophobia, paresthesia
failure, some leading to death or of normal) (4%), urinary tract transaminases to clinical
liver transplant; Serious skin infection (3%) bleeding; Angioedema; Hepatic/Renal: Transient
hepatitis, jaundice, cholestasis, Erythema multiformae-like
reaction (Stevens–Johnson Other: Rhinitis (9%), upper and fulminant hepatic failure, increases in serum
syndrome, toxic epidermal reaction, serum-sickness-like AST(SGOT), ALT (SGPT)
respiratory tract infection (8%), including fatalities; Rare cases reaction; Photosensitivity;
necrolysis); Changes in ocular sinusitis (7%), cystitis (3%), of anaphlyaxis (including and alkaline phosphatase
lens and retina; Agranulocytosis; Lupus erythematosus, lupus-
myalgia (3%), asthenia (2%), angioedema, face edema and like syndrome or exacerbation Other: Less than 1%:
Thrombocytopenia, angioedema fever (2%), pain (2%), tremor pruritis); QT prolongation, Arthralgia, fever and chills,
and allergic reactions (including of preexisiting lupus
(2%), herpes zoster (2%), torsade de pointes; Seizures; erythematosus; Toxic dyspnea, tinnitus, impotence,
anaphylaxis); Transient pharyngitis (2%) Dizziness; Alopecia; Exfoliative changes in sweat patterns,
decreases in absolute epidermal necrolysis;
Post-marketing experiences (rare): skin disorders including Proteinuria, nephrosis; alopecia, signs of increased
lymphocyte count; cases of Stevens–Johnson syndrome intracranial pressure,
severe neutropenia; Precipitation Rare cases of serious hepatotoxicity Hepatotoxicity; Menstrual
and toxic epidermal necrolysis; irregularity, amenorrhea; hemolytic anemia,
and exacerbation of cutaneous including liver failure and death; Leucopenia, including thrombocytopenia,
and systemic lupus Vomiting; Peripheral edema, Estrogen-like effects in
neutropenia and agranulocytosis; children; Transient diminution leucopenia
erythematosus; malaise; fatigue; congestive heart failure, Thrombocytopenia;
vomiting; arthralgia; myalgia; pulmonary edema; Peripheral of hearing; Reversible Post-marketing experiences
Hypercholesterolemia, leucopenia; Elevated (rare):
hair loss; neuropathy; Menstrual disorders; hypertriglyceridemia,
Reversible increases in hepatic concentrations of porphyrins in Hepatotoxicity (hepatocellular,
hypokalemia; Dyspepsia, feces and erythrocytes;
enzymes, hepatitis, liver failure; vomiting, and taste perversion cholestatic or mixed pattern),
Hypokalemia, Tachycardia, flushing when typically reversible, death
kypertriglyceridemia; Alopecia; concomitant with alcohol, and rarely; Bilateral
Allergic reactions (pruritis, rash, potentiation of alcohol effects gynecomastia with breast
urticaria, angioedema, tenderness in some men;
anaphlaxis); Stevens–Johnson Adrenocorticol insufficiency;
syndrome; Anaphylactic, Transient decrease in serum
anaphlactoid and allergic cholesterol, alterations in
reactions; Photosensitivity; serum triglyceride
Neutropenia; Congenital concentrations; Anaphylactic
abnormality including skeletal, reactions after first dose;
genitourinary tract, Neuropsychiatric
cardiovascular and ophthalmic disturbances including
malformations as well as suicidal tendencies, severe
chromosomal and multiple depression; Hypertension in
malformations (causal relation to several subjects receiving
itraconazole not established) 400 mg every 6–8 h for
metastatic prostate
carcinoma; Disulfiram
reactions (flushing, rash,
peripheral edema, nausea,
headache) when ingesting
alcohol
Mycopathologia (2008) 166:353–367
Mycopathologia (2008) 166:353–367 359

Oral itraconazole is indicated for the treatment of griseofulvin, as ketoconazole has been associated
adults with dermatophyte onychomycosis of the with a potential for liver damage [17]. Patients using
toenails and/or fingernails, and for systemic mycoses oral ketoconazole should be tested for signs of liver
such as blastomycosis, histoplasmosis, and aspergil- dysfunction prior to initiating therapy. While on
losis. Liver function monitoring should be considered therapy, patients should be closely monitored for
for any subject, and testing is required for any subject signs of hepatotoxicity, both clinically and biochem-
with pre-existing hepatic function abnormalities or ically, using liver function tests, including serum
previous experience of liver toxicity with other AST, ALT, alkaline phosphatase, gamma-glutamyl-
medications [13]. Itraconazole is metabolized transferase, and bilirubin (e.g., biweekly during the
through the CYP3A4 pathway and thus has potential first 2 months of therapy; monthly or bimonthly
for numerous drug interactions, limiting its use in afterwards) [17]. Patients should be instructed to
some patients. Itraconazole is prohibited in patients report any symptoms of liver dysfunction such as
showing ventricular dysfunction such as current or persistent nausea, anorexia, fatigue, vomiting, right
past congestive heart failure [13]. A current country- upper abdominal pain or jaundice, dark urine or pale
specific product monograph should be consulted for stools.
complete listing of known drug interactions, warn-
ings and monitoring requirements prior to
prescribing. Capsules must be taken with a meal, or Treatment of Tinea Pedis/Tinea Manuum
cola beverage to ensure adequate absorption [13, 21].
Oral fluconazole is indicated for the treatment of Topical formulations of terbinafine, butenafine, mico-
(1) vaginal candidiasis (vaginal yeast infections due nazole, econazole, ketoconazole, clotrimazole,
to Candida species), (2) oropharyngeal and esopha- oxiconazole, and ciclopirox are the most frequently
geal candidiasis, and (3) cryptococcal meningitis used topical preparations for tinea pedis/tinea man-
[14, 22]. Though not specifically indicated for uum [23–25] (Table 1). Topical formulations may be
dermatophyte infection, fluconazole has been docu- used for milder, limited presentations. Many topical
mented in the medical literature as a successful agent agents (e.g., miconazole nitrate 1%, ciclopirox ola-
for all types of superficial dermatophytoses, particu- mine 1%, naftifine hydrochloride 1%, sulconazole
larly tinea capitis. When fluconazole and cyclo- nitrate 1%) provide antibacterial activity and may be
sporine are given concomitantly, careful monitoring preferred where bacterial superinfection is suspected.
of cyclosporine concentration and serum creatinine Formulations allowing once-daily application rather
concentration is recommended [14]. Similarly, blood than twice-daily (e.g., naftifine 1% cream, bifonazole
glucose levels should be closely monitored when 1%, ketoconazole cream 2%) may aid patient com-
using oral hypoglycemics concomitantly with fluco- pliance and subsequent efficacy. There are no
nazole, and prothrombin time should be monitored approved treatments specifically for tinea manuum;
for patients receiving coumarin-type anticoagulants treatments for tinea pedis are effectively used to treat
concomitantly with fluconazole. tinea manuum.
Oral griseofulvin is indicated for the treatment of Chronic infection may warrant the use of oral
tinea infections of the skin, hair, and nails [15, 16]. antifungals, particularly if previous topical regimens
As with other oral antifungal agents, the use of have failed. Off-label use of oral itraconazole,
griseofulvin is not justified for the treatment of tinea terbinafine, or fluconazole may be practical where
infections that would be expected to respond satis- the tinea involvement is extensive and application of
factorily to topical antifungals. During prolonged a topical is not feasible [26]. Studies have shown that
griseofulvin therapy, periodic assessment of renal, oral terbinafine and itraconazole may be the most
hepatic, and hematopoietic functions should be effective treatments, and a higher cure rate has been
performed [15, 16]. shown with topical allylamines than with topical
Oral ketoconazole is indicated for the treatment of azoles [23, 27]. Terbinafine 250 mg/day has been
patients with severe recalcitrant cutaneous dermato- used for tinea pedis with a duration of 2–6 weeks
phyte infections who have not responded to topical [11, 28]. Itraconazole regimens of 100 mg/day for
therapy or oral griseofulvin, or who are unable to take 30 days or 4 weeks, 400 mg daily for 1 week, and

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360 Mycopathologia (2008) 166:353–367

200 mg/day for 2–4 weeks have been reported [11, reported to be effective [28, 40, 41]. The dose of
26, 29]. The dose of fluconazole for tinea pedis most fluconazole suggested for tinea corporis/tinea cruris
frequently reported is 150 mg once weekly adminis- is 150–300 mg once weekly administered for
tered for 2–6 weeks [30–37]. 2–4 weeks [28]. These oral agents are preferred over
Though oral griseofulvin is approved for treatment ketoconazole, due to the potential for hepatic side
of tinea infections that are not expected to respond effects with ketoconazole use, and griseofulvin is not
satisfactorily to topical antifungals, griseofulvin has recommended as it does not adequately bind the
lower efficacy than the newer antifungals, poor keratin in the stratum corneum, reducing efficacy
keratin adherence, and narrow-spectrum activity [28]. Where griseofulvin is used for these indications,
(dermatophytes only) which may be a limitation the suggested dosage is 250 mg twice daily until cure
where superimposed bacterial infection is present is reached [28]. Similarly, where the decision is made
[11]. Where griseofulvin dosing is used, the sug- to provide ketoconazole, the suggested dosage is
gested dosage for tinea pedis is 660 or 750 mg daily 200–400 mg daily for 4–8 weeks [28].
for 4–8 weeks [11]. Similarly, use of ketoconazole
tablets has been discouraged due to the potential for
hepatic side effects; however ketoconazole dosing of Treatment of Tinea Capitis
200–400 mg daily for 4–8 weeks has been used for
the treatment of tinea pedis infection [11, 17, 22, 28]. Unlike most dermatophytoses, topical monotherapy is
Prevention of reinfection is important, and educa- not recommended for tinea capitis. Oral therapy is
tion of the patient on proper foot hygiene is essential. required to adequately treat tinea capitis, as they are
Patients should avoid walking barefoot in communal able to penetrate the infected hair shaft where topical
areas such as bathrooms, showers or swimming areas, therapies cannot (Table 1). Topical antifungals such
and ensure that feet are dried thoroughly after as antifungal shampoos (ketoconazole, selenium
bathing, showering, or swimming [38]. Occlusive sulfide, povidone iodine, zinc pyrithione) may be
footwear should be avoided, or shoes should be used as adjunct therapy with or without oral antifun-
alternated every 2–3 days, with frequent sock gals to prevent reinfection or to treat asymptomatic
changes to reduce the moisture in the foot environ- carriers [38, 42, 43].
ment [38]. Griseofulvin is the only oral antifungal treatment
approved for use in tinea capitis in North America;
however use of terbinafine, itraconazole, and fluco-
Treatment of Tinea Corporis/Tinea Cruris nazole for tinea capitis are also reported extensively
in the medical literature. The efficacies and safety
Topical therapies for treatment of tinea corporis/tinea profiles of terbinafine, itraconazole, and fluconazole
cruris include terbinafine, butenafine, econazole, are similar to griseofulvin, and may be used where
miconazole, ketoconazole, clotrimazole, and ciclopi- griseofulvin therapy has failed. Itraconazole, terbina-
rox [39] (Table 1). Topical formulations may fine, and fluconazole have the advantage of shorter
eradicate smaller areas of infection, but oral therapy treatment durations compared to griseofulvin [42].
may be required where larger areas are involved or Dosages are typically given on a weight-based scale,
where infection is chronic or recurrent [28]. and infections with Microsporum may require higher
Off-label use of oral antifungals may be practical dosing than infections with Trichophyton, or longer
where the tinea involvement is extensive and appli- therapy durations [42, 44]. Oral suspensions are
cation of a topical is not feasible [26]. Oral available for griseofulvin, itraconazole, and fluco-
itraconazole, terbinafine, and fluconazole have been nazole to aid pediatric dosing (Table 3). Terbinafine
used successfully in the treatment of tinea corporis/ and griseofulvin tablets can be crushed, and itraco-
tinea cruris. Terbinafine 250 mg/day has been used in nazole capsules can be opened, and added to a fatty
this clinical context with a regimen generally of food such as peanut butter [45, 46].
2–4 weeks [28]. A continuous itraconazole regimen Griseofulvin suggested dosing is 20–25 mg/kg/day
of 200 mg/day for 1 week is recommended, though a using the microsize formulation, for 6–12 weeks [43]
regimen of 100 mg/day for 2 weeks has also been (Table 3). Where the ultramicrosize formulation is

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Table 3 Tinea capitis dosing in childrena
Regimen Duration Weight (kg)
10–20 21–30 31–40 41–50 [50
Mycopathologia (2008) 166:353–367

Terbinafine (continuous) 5 mg/kg/day 2–4 weeks 62.5 mg qd 125 mg qd 125 mg qd 250 mg qd 250 mg qd
Itraconazole (continuous) 5 mg/kg/day 2–4 weeks 100 mg qd, every 100 mg qd 100 mg qd/bid on 200 mg qd 200 mg qd
second day alternate days
Itraconazole (pulse)b Capsules: 5 mg/kg/day 1–3 pulses 100 mg qd, every 100 mg qd 100 mg qd/bid on 200 mg qd 200 mg bidc
second day alternate days
Oral suspension: 3 mg/kg/day 1–3 pulses
Fluconazole (continuous) Oral suspension:6 mg/kg/day 20 days
Fluconazole (pulse)d Oral suspension:6 mg/kg/day 8–12 weeks
Griseofulvin (continuous) Microsize: 20–25 mg/kg/day 6–12 weeks
Ultramicrosize: 10–15 mg/kg/day 6–12 weeks
Oral suspension: 15–25 mg/kg/daye 6–12 weeks
a
Durations of treatment are for Trichophyton tonsurans infection. Longer durations are needed for Microsporum canis infections. Dosing based on US FDA regulations—consult
country-specific prescribing information prior to providing dosages. qd: once daily; and bid: twice daily
b
Itraconazole pulses are given for 1 week, with 3 weeks ‘‘off’’ before starting the next pulse
c
No standard has been established in clinical trials for tinea capitis for children[50 kg, and use varies from once-daily as with continuous regimen to twice-daily 200 mg dosing
d
Fluconazole pulses are 1 day on, 6 days off, before beginning next pulse
e
Dosing based on Grifulvin V suspension 125 mg/5 ml
361

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362 Mycopathologia (2008) 166:353–367

used, a dose of 10–15 mg/kg/day is suggested, as it is initiated, particularly children in higher grades where
more rapidly absorbed than the microsize form [43]. little physical contact between students is expected
The oral suspension (microsize griseofulvin) contains [38, 43].
125 mg per 5 ml. Treatment should be continued for
2 weeks after the resolution of clinical symptoms.
Mycological cure rates and effective therapy rates are Tinea Unguium (Onychomycosis)
generally high, being in the range of 80–95% and
88–100%, respectively [26, 43]. Distal-lateral subungual onychomycosis is difficult to
The standard terbinafine dosing regimen for tinea cure and has a high rate of recurrence [24, 55].
capitis daily dosing is based on weight (less than Fingernails may show higher treatment success rates
20 kg = 62.5 mg; 20–40 kg = 125 mg; greater than than toenails due to faster rates of outgrowth, and
40 kg = 250 mg per day) (Table 3). The duration of suggested dosing regimens are shorter for fingernail
therapy is generally 4 weeks, though pulse dosing infection than toenail infection [56].
regimens and shorter durations have also been Where the nail has been injured or shows other
reported to be effective [43, 47, 48]. Higher dosages abnormal growth patterns, nail outgrowth may be
or longer duration of therapy may be required for slow, and the nail may never regain a normal
M. canis infection [43]. Limited studies suggested appearance though the infection may be eradicated.
that doses greater than 4.5 mg/kg/day might increase Furthermore, relapse of infection is frequently noted.
cure rates in both Trichophyton and Microsporum Nail growth should be assessed, and patient expec-
infections, with duration of therapy being less tations should be discussed, so the patient
important [49, 50]. understands that successful treatment is unlikely to
Both continuous and pulse regimens of itraconaz- occur quickly, that long-term follow-up is necessary
ole have been used to treat tinea capitis. The to catch any relapses in the early stages, and that the
continuous regimen is 5 mg/kg/day for 4 weeks, nail may not return to a normal appearance even
and the pulse therapy regimen is 5 mg/kg/day for though the infection may clear.
1 week a month, given for 2–4 months [43] Routine nail debridement may be complementary
(Table 3). Where the oral solution is used, dosage for subjects using oral therapy as well as topical
is reduced to 3 mg/kg/day, whether used as contin- therapy, particularly where the nail is thickened, or
uous or pulse therapy [43, 51]. where the infection presents as a dermatophytoma,
A limited number of studies have shown that spike or lateral infection. A recent clinical trial
therapy with fluconazole 6 mg/kg/day lasting 2– (IRON-CLAD) demonstrated that elderly subjects
3 weeks can effectively treat tinea capitis [42, 43] receiving aggressive debridement in conjunction with
(Table 3). A comparative study of 5 mg/kg/day for a 12-week course of oral terbinafine showed higher
4 weeks showed similar efficacy to griseofulvin rates of clinical improvement than that of subjects
6 mg/kg/day for 6 weeks [52]. Once weekly therapy who did not receive debridement [57]. Subjects
with fluconazole for tinea capitis has also been found receiving debridement also showed higher rates of
to be effective [53, 54]. treatment satisfaction [58]. Caution must be taken not
Transmission of infection from patients and from to damage the underlying skin during debridement,
symptom-free carriers has been a concern for clini- particularly in subjects who are vulnerable to severe
cians treating tinea capitis. Adjunct therapies can be lower limb complications, such as diabetics or
provided to the patient and family members to control individuals with reduced lower limb profusion.
transmission. Infection frequently may initiate from Nail avulsion is one of the traditional options
contact with animals, and treatment of pets may be available to manage onychomycosis. Atraumatic nail
required. Patients and family members should be removal with urea or bifonazole compounds is
counseled to avoid sharing items such as caps, combs, preferred to surgical removal, as surgical removal
and toys [42, 43]. Hats, combs, pillows, blankets, has some potential to permanently alter the nail bed,
scissors, etc, may be disinfected with bleach [38]. and may also be painful for the subject to undergo
Most clinicians agree that infected children do not [59–61]. Removing the infected nail plate eliminates
need to be kept out of school once treatment is most of the invading fungi and allows the underlying

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Mycopathologia (2008) 166:353–367 363

surface to be treated with conventional topical 48 weeks, though some trials showed success with
antifungal agents [62]. Partial nail plate avulsion less frequent use (e.g., 3 times per week) [65, 66].
may be appropriate in cases of superficial white Ciclopirox lacquer should be used with routine nail
onychomycosis and early distal subungual onycho- debridement to provide effective delivery of drug to
mycosis, although these management options have the infected area and to reduce the burden of fungal
not been examined in large randomized, controlled material [66]. The mycological cure rate at week 48
trials [59, 63]. The utility of topical agents as was 33% in the pivotal US clinical trials; other trials
adjunctive therapy following nail avulsion also has which were mostly open-label showed mycological
not been conclusively established, though some cases cure rates of 47–67% [65, 66]. Though mycological
may benefit [64, 65]. cure rates are reasonable, overall success rates may
As with tinea pedis, proper foot and nail hygiene be quite lower [65]. Its use is not associated with any
may help prevent reinfection. Patients should avoid of the potential adverse effects that might occur with
walking barefoot in communal areas such as bath- oral antifungals, for example hepatotoxicity and
rooms, showers, or swimming areas, and ensure that cutaneous reactions [66].
feet are dried thoroughly after bathing, showering or Amorolfine 5% nail lacquer is approved for
swimming [38]. Nails should be kept short and clean. monotherapy of mild onychomycosis with no matrix
Shoes should fit properly and socks should be made involvement. Application is typically once or twice
from absorbent material such as cotton. Disinfection weekly, for 6–12 months. Pivotal trials indicated that
of socks and shoes should be performed, and amorolfine 5% provided mycological cure rates of
laundering of socks in 60C water with an all- 60–76% with once or twice weekly use, and very few
purpose detergent may also aid in destruction of adverse events were associated with its use, with all
fungal elements [61]. events being minor and confined to the application
site [2, 56, 65, 67]. Though mycological cure rates
Topical Therapy are reasonable, overall success rates may be quite
lower [65].
Topical therapy may be indicated for cases of mild to Topical medications such as terbinafine may be
moderate infection (B50% of distal end affected) useful as an adjunctive therapy for severe infections
where the matrix is not involved, and few (3–4) nails being treated with oral terbinafine, or where paro-
are affected [2]. Few adverse events are expected nychia is present [2]. Topical monotherapy with
with topical therapy compared to oral therapy [2]. terbinafine or azoles would not be expected to
Two topical medications formulated as lacquers provide effective therapy in more severe cases of
provide good penetration of the nail unit and are infection, particularly where the matrix is involved.
approved for use in onychomycosis as monothera- Use of topical azoles or allylamines as prophylactic
pies: ciclopirox and amorolfine [2, 65]. The lacquer therapy has rarely been reported; limited reports with
formulations may be superior to other topical formu- miconazole powder did not show successful prophy-
lations, as the volatile vehicles leave an occlusive laxis of infection [68].
film of concentrated drug on the nail, providing a Tinea pedis is frequently seen in conjunction with
fixed drug gradient, and increasing hydration of the toenail onychomycosis, and onychomycosis infection
nail which further aids diffusion into the underlying can spread to other parts of the body as well, such as
nail structures [65]. However, while it is practical to in the two feet-one hand syndrome [69]. Topical
use nail lacquers in situations where few nails are adjunctive therapy may be warranted for such cases
involved, an oral antifungal agent should be consid- to clear up and prevent further spread of infection.
ered when a greater number of nails are involved,
greater areas are involved, or infection includes the Oral Therapy
matrix region.
Ciclopirox nail lacquer 8% solution is approved Though griseofulvin is approved for tinea infection of
for the management of mild to moderate onychomy- the nails, its affinity for keratin is low and long-term
cosis without lunula involvement caused by therapy is required [21]. Efficacy in the treatment of
T. rubrum and should be applied once daily for onychomycosis is also low, and the newer azole and

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364 Mycopathologia (2008) 166:353–367

allylamine agents have largely replaced griseofulvin Discussion


for this indication [21]. Ketoconazole is not recom-
mended for therapy of onychomycosis due to the Oral therapy may be considered over topical therapy
potential for hepatotoxicity (blocking human CYP- for patients with large areas of infection extent, where
dependent demethylation of ergosterol at higher infection presents with unusual severity or persis-
concentrations), and to the availability of alternative tence, or where patients may have problems
oral treatments [21]. Fluconazole has shown high complying with daily topical application. Similarly,
efficacy, low relapse rates, and usefulness with yeast patients who are immunocompromised may be pro-
coinfection; however, there have been few studies on vided with oral treatment where prompt, thorough
this treatment method [39, 56]. resolution of infection is mandatory.
The oral therapy regimens for onychomycosis are Topical corticosteroid use is not recommended for
as follows: terbinafine 250 mg/day for 12 weeks dermatophytosis, as it may lead to suppression of
(toenails) or 6 weeks (fingernails only); and itraco- physical signs of infection, with lack of symptoms
nazole 200 mg twice daily as pulse therapy (one pulse: being wrongly associated with clearance of infection,
1 week of itraconazole followed by 3 weeks without leading to treatment relapse [28].
itraconazole) using 2–3 pulses (two pulses: fingernails; Relapse of therapy has been noted with most types
three pulses: toenails) [21, 61]. In countries where of dermatophyte infection. Infection transmission
fluconazole is approved for the treatment of onycho- from symptom-free carriers like family members
mycosis, the most frequently used schedule is and pets may need to be controlled with adjunct
fluconazole 150–300 mg once weekly given until the therapies and techniques; fomites such as hats and
abnormal-appearing nail has grown out (fingernails: combs must also be treated. Patients must be
approx. 3–6 months; toenails: approx. 9–12 months) encouraged to complete a full treatment cycle, as
[21]. infection can be present without visible symptoms.
Use of pulsed terbinafine regimens has been Microscopic examination and culture are required
suggested as a method to improve the safety profile to confirm elimination of the pathogen; however, there
of oral terbinafine; however, unlike itraconazole, the are limitations with basing ‘cure’ on negative culture
efficacy of pulsed terbinafine has not been conclusively findings as well. There is a high false negative culture
established compared to continuous regimens [70]. rate, and thus there is a question of whether new
episodes of infection are new infections, or relapses of
Combination Therapies previous infection. Limitations of standard microscopy
and culture methods have been recognized for years,
The cure rates for onychomycosis are lower than but until recently no other reliable methods of fungus
desirable, and it has been recognized that there is a identification have been available. Reports on the use
high rate of relapse following successful treatment of molecular biology methods to identify fungal DNA
[61, 71]. Efforts to improve the cure rates have most are increasing [78–82]. These molecular methods
recently involved various combinations of antifungal provide fast identification relative to the standard
therapies. It has been suggested that oral antifungals microscopy/culture methods. It remains to be seen
with differing mechanisms of action may provide what impact such analysis may have on fungal
synergistic effects leading to increased fungicidal treatment. Greater use of such analyses can be expected
activity (i.e., terbinafine/itraconazole combination in future, particularly if it can be conclusively demon-
therapy) [65, 72, 73]. Use of a topical medication strated that such methods can provide an analysis of
(amorolfine, ciclopirox nail lacquer, …) in combina- viable fungus present in nails with higher reliability
tion with an oral antifungal may improve the efficacy than standard microscopy/culture methods. Reassess-
by providing increased routes of drug penetration, ment of oral antifungal efficacy measures, particularly
and increase efficacy may also improve cost-benefit in onychomycosis, may be called for if more reliable
rates for severe onychomycosis treatment [26, 65, 72, identification methods become accepted in general
74–77]. These combination methods require further dermatology treatment.
study to determine efficacy, and are not currently Though there is concern over the high relapse/
accepted treatment methods. reinfection rates in onychomycosis, prophylactic

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Mycopathologia (2008) 166:353–367 365

regimens for onychomycosis have not been developed. 15. Griseofulvin (Systemic). In: Drug information for the
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