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Fluconazole for common tinea infection: An updated review of evidence and treatment guidance
Introduction
Dermatophytosis is the most common superficial fungal infection of the skin or skin derivatives. It is caused by filamentous fungi called dermatophytes prone to attack and multiply in keratinized tissue such as skin, hair, and nails. Dermatophytosis is an umbrella term for tinea pedis, tinea corporis, tinea cruris, etc.[1] Data suggests that about 20-25% of the world population may be affected by dermatophytosis. [2] In India, the prevalence of dermatophytosis ranges from 36.6–78.4%. [1] Recalcitrant tinea infection referred to at least two episodes of recurrence within 6 weeks has caused dermatophytosis to become a chronic dermatological condition in India. [3] In one study, tinea corporis and tinea cruris accounted for 21.32% and 12.32% of the cases, while 11.84% cases of recalcitrant dermatophytosis were observed. [2], [4], [5] Dermatophytosis is one of the most common groups of skin diseases encountered by dermatologists in out-patient department (OPD). [3]
Symptoms include erythema, plaques, vesicles, small papules, and fissures. Diagnosis is difficult due to new and varying clinical presentation such as unusual large lesions, multiple site lesions, ring within ring lesions and corticosteroid modified lesions. Late diagnosis or negligence can cause dermatophytes to become invasive, leading to deeper and disseminated infection impacting overall quality of life. India`s humid and warm climate, make it the ideal place for fungal infection. High usage of corticosteroids, more immunocompromised patients and agricultural infection, further contribute to the rising burden. [1]
The current scenario is characterized by changing pattern of the dermatophyte isolates, with Trichophyton mentagrophytes complex emerging as the major pathogen. Furthermore, few isolates are multidrug resistant. [6] Management of the disease has become clinically challenging in India due to changing pathophysiology and symptoms. With the rising trend of recalcitrant dermatophytosis, low mycological cure rate and antifungal resistance, this mycotic skin infection has turned into an alarming issue. [1]
Management of dermatophytosis with topical antifungals is becoming less clinically effective. First, due to recurrence and secondly, non-compliance towards topical antifungals has been observed due to its frequent need of application (two-three times a day). [7] Azoles, a category of antifungals is widely prescribed in India. [3] Ketoconazole is less frequently prescribed due to its hepatotoxic effects and use of griseofulvin is limited to tinea capitis. [8] Fluconazole, an oral antifungal is effective and safe for the management of dermatophytosis including recalcitrant cases. In India, majority of general physicians (GPs) prefer Fluconazole (150 mg weekly) as their first line oral antifungal drug for the treatment of dermatophytosis in both government and private sectors, according to a survey. This review would help dermatologists and general physicians in prescribing oral fluconazole based on clinical efficacy, safety, pharmacokinetics, and guideline recommendations.
Pharmacokinetic Properties
Absorption and distribution
Bioavailability of orally administered fluconazole is over 90% in healthy volunteers. Many of the clinical advantages ascribed to fluconazole relate to its pharmacokinetic profile which differs substantially from older azole antifungals. In humans, the volume of distribution approximates that of total body water (0.7-0.8 L/kg). Plasma protein binding of fluconazole is low (approximately 11%) compared to other azole antifungals which are highly bound. Thus, most fluconazole circulates as free drug.[9] Relevant pharmacokinetic parameters are summarized in [Table 1].
The Cmax and AUC data from a food-effect study indicated that exposure to fluconazole is not affected by food. Hence fluconazole may be taken without regard to meals.[10]
Metabolism and elimination
In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites. In a special population, the elimination half-life (t½) for fluconazole is 30 hours and is prolonged in patients with renal impairment. [10]
Special population
For renally impaired patients dose modification is required while administering oral fluconazole. In severe renally challenged cases hemodialysis or peritoneal dialysis is an alternative for drug elimination. During pregnancy fluconazole should be administered with precaution as it is known to cause adverse effects like teratogenicity or embryocidal effects on the foetus. Fluconazole has shown beneficial effects in children from 6 months to 13 years of age. Fluconazole should be avoided in infants less than 6 months. [10]
Drug interaction
Fluconazole is known to reduce the clearance of antipyrine. Though, fluconazole 50 mg daily had no effect on the metabolism of antipyrine in a study of 7 healthy volunteers however, few drug-drug interactions have been reported with fluconazole. Careful monitoring and dosage adjustment of phenytoin and possibly of oral anticoagulants, sulphonylureas and cyclosporin may be required, particularly if higher fluconazole dosages (about 200 mg/day) are used.[9] [[Table 2]]
Pharmacodynamics
Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. Regarding invitro activity and in clinical Infections, fluconazole has been shown to be active against most strains of the following microorganisms – Candida albicans, Candida glabrata (Many strains are intermediately susceptible), Candida parapsilosis, Candida tropicalis and Cryptococcus neoformans. [10] The antifungal activity of any azole works by inhibiting sterol membrane synthesis by fungal cytochrome P450 enzyme. Ketoconazole also works by inhibiting cytochrome P450, while fluconazole has minimal effect on these enzymes implying to be free of adverse effects. [9] The nitrogen of the azole ring is thought to bind to the haem moiety of the fungal cytochrome P450 enzyme lanosterol 14α-demethylase, thereby halting conversion of lanosterol to ergosterol. [[Figure 1]]
|
Dosage (per day) |
N |
Route |
Cmin (mg/L) |
Cmax (mg/L) |
Tmax (h) |
AUC (mg/Lxh) |
t½ (h) |
Vd (L/kg) |
|
Healthy volunteers |
||||||||
|
100 mg |
20 |
IV |
|
6.3 |
|
107a |
36 |
0.71 |
|
200 mg |
15 |
PO |
|
10.1 |
1.5 |
170b |
31 |
|
|
400 mg |
15 |
PO |
|
18.9 |
1.5 |
350b |
31 |
|
|
Patients |
|
|
|
|
|
|
|
|
|
400 |
3 |
PO |
21-23 |
30.6 |
3.3 |
|
37.2 |
|
|
Drug level of fluconazole is decreased by |
Fluconazole decreases level of these drugs |
Fluconazole increases level of these drugs |
|
Rifampicin |
Oral contraceptives |
Sulfonylurea, nifedipine, theophylline, NSAIDs, warfarin, cyclosporine |
|
S. No. |
Trial design |
N |
Indication |
Intervention and treatment duration |
results of fluconazole |
Ref. |
|
|
primary |
secondary |
|
|||||
|
1 |
Single arm study |
70 |
Tinea pedis |
Fluconazole 150 mg once in every 7-10 days. (4-5 doses in) 28 days-40 days |
1.Mycological eradication at the end of study- 87% and at the follow-up was 78%. 2.Clinical eradication rate was 74% post treatment and 77% at the end of follow up. |
1. Total pathogen eradication 86.7%. 2. Adverse events occurred in 5/70 |
|
|
2 |
multicentre open non comparative |
95 |
Tinea corporis/cruris and cutaneous candidiasis |
Fluconazole 150 mg / week (4-5 doses in) 28 days-40 days |
1. mycological eradication was 99% post treatment and 89% after follow up. 2. clinical eradication 92% post treatment and 88% after follow-up. 3. Cure rate post treatment was 82%. 4. Total pathogen eradication 98.8% |
dermatological effects (3), CNS (1), GI effect (1), Insomnia (1), moderate urticaria (1) |
|
|
3 |
open, non-comparative study, |
115 |
Tinea corporis and Tina cruris |
Fluconazole 150 mg/week 2-4 weeks |
1. Reduction in the total symptom severity score. 2. Overall clinical efficacy cure rate 1 week after last dose 41% and 3 weeks after last dose was 71%. 3. overall microscopic mycological cure rates in 40 patients, after 3 weeks last dose 55 patients cured |
10 AE in 7/115 patients |
|
|
4 |
open, non-comparative study |
20 |
Tinea Corporis, Tinea Cruris, and Tinea Pedis |
one dose of fluconazole 150mg in 7-10days 2-4 weeks |
Fluconazole on Tinea Corporis/Cruris result: 1. Clinical cure rates 100% post treatment in 4th dose and 95% long term follow up clinical cure rates 2. mycological eradication rates were 100% post treatment in 4 dose and 95% Follow up eradication |
Fluconazole on Tinea Pedis result: 1. Clinical cure rates 42% post treatment in 4th dose and 70% long term follow up clinical cure rates 2. mycological eradication rates were 75% post treatment in 4 dose and 75% follow up eradication rate |
|
|
5 |
multicentre, open, noncomparative study |
521 |
Tinea Corporis, Cruris or Pedis or Cutaneous candidiasis |
Fluconazole 150 mg/week 2-6 weeks=avg 4.65 weeks |
Clinical success rate: at the end of study=96%, follow-up=92%; Lesion cured= 68% (331/418), reduction in lesion=28% (136/418); After follow-up, improved after 1 week 36% and after 3 weeks 6% |
1. good tolerability 2. 7 patients (1.3%) discontinued therapy |
|
S.No. |
Trial design |
N |
Indication |
Intervention and treatment duration |
results of fluconazole |
Ref |
|
|
Primary |
Secondary |
|
|||||
|
1 |
Open label, comparative study |
391 |
Tinea corporis, tinea cruris, tinea pedis or cutaneous candidiasis, |
fluconazole 150mg /week or topical Clotrimazole 1% BD 2-4 weeks |
1. Fluconazole with clinical response of 85%, 90%, 81%,100% post treatment and 93%, 78%, 82%, 100% during follow up in T. corpis, T. cruris, T.pedis and cutaneous candidiasis. 2. Mycological response of fluconazole was 75%, 90%, 79%, 100% post treatment and 83%, 72%, 69%, 100% during follow up in T. corpis, T. cruris, T.pedis and cutaneous candidiasis. |
Fluconazole had 4% of AE observed (probably/ possibily) out of which 2.6%GI, 1% dermatitis/ urticaria 0.5% bronchospasm and 2.1% diarrhea, dyspepsia,etc. |
|
|
2 |
double-blind, parallel comparative study |
230 |
tinea corporis or tinea cruris. |
fluconazole 150mg/ week or griseofulvin500 mg once daily 4-6 weeks |
1. Clinical cured rates 74% and 62% in fluconazole and grisofulvin groups. on day 42-44. 2. improved clinical rates 18% and 22% in both groups. 3. mycological cured rates were 78% and 80% in fluconazole and grisofulvin group |
7.5% and 12.5% patients in fluconazole and grisofulvin group had adverse effects. |
|
|
3 |
single observer open comparative study |
90 |
tinea corporis, tinea cruris, and tinea facie |
A—Terbinafine 250 mg once daily for 2 weeks B—Terbinafine 250 mg twice daily for 1 week C—Fluconazole 150 mg weekly for 4 week |
Non-significant difference in mycological and clinical cure rate in three groups Clinical cure rate: Group A – 80% Group B – 73.33% Group C – 63.3% Mycological cure rate at 4 weeks: Group A – 93.3% Group B – 86.7% Group C – 83.3% |
Gastrointestinal side effects Group A+B – 16.7% Group C -20% |
|
|
4 |
randomized double blind clinical trial |
30 |
T. corporis and T .cruris |
Fluconazole 150 mg weekly for 4 weeks or Terbinafine 250 mg daily for 2 weeks. |
At the end of the treatment, 64.3% of the subjects in Fluconazole group developed clinical and laboratory responses, while the second group developed 75% clinical and 81.3% laboratory cure. One month later, 64.3% in the Fluconazole group were cured, while in the other group, 87.5% were cured |
|
|
System |
Adverse event |
|
Immunologic |
In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been reported. |
|
Body as a whole |
Asthenia, fatigue, fever, malaise |
|
Cardiovascular |
QT prolongation, torsade de pointes. |
|
Central nervous system |
Seizures, dizziness. |
|
Hematopoietic and lymphatic |
Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia. |
|
Metabolic |
Hypercholesterolemia, hypertriglyceridemia, hypokalemia |
|
Gastrointestinal |
Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting. |
|
Other senses |
Taste perversion. |
|
Muscoskeletal |
myalgia |
|
Nervous system |
Insomnia and somnolence both? tremor, vertigo. |
|
Skin and appendages |
Acute generalized exanthematous-pustulosis, drug eruption, increased sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis, alopecia. |
|
Guideline |
Condition |
Fluconazole Dose |
Minimum duration |
Precautions |
|
|
Adults |
Children |
||||
|
IADVL ITART 2020 |
Naïve tinea corporis and tinea cruris |
50-100 mg/day |
3-6 mg/kg/day |
4 weeks |
hepatotoxicity |
|
150-200 mg once weekly |
8 weeks |
||||
|
CH/SMT/RCL tinea corporis and tinea cruris |
100mg/day |
6 weeks |
|||
|
150 mg/ thrice weekly * |
8 weeks |
||||
|
AFP guideline (2014) |
Extensive disease, failed topical treatment, immunocompromised patients, or severe moccasin-type tinea pedis |
6 mg/kg/ day |
- |
3-6 weeks |
|
|
6 mg/kg once weekly |
|||||
|
Indian review article |
Tinea corporis or Tinea Cruris |
150-300 mg/week |
- |
3-4 weeks |
|
|
Tinea pedis |
150 mg/week |
4 weeks |
|
Patient characteristic |
Choice of antifungal |
|
Hepatic dysfunction |
Oral fluconazole* or topical antifungals |
|
Children under 2 years |
Oral antifungal or topical antifungals with established safety |
|
Children above 2 years |
Oral fluconazole, terbinafine, itraconazole, and griseofulvin or topical antifungals with established safety |
|
Lactating mother |
Oral fluconazole or topical antifungals |
Therapeutic Efficacy
Clinical efficacy and safety of oral fluconazole 150 has been well established in the management of tinea corporis, tinea cruris and tinea pedis.[[Table 3], [Table 4]]
Tolerability
Fluconazole is generally well tolerated. In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain. The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving fluconazole for 7 or more days in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%. [10] In addition, the following adverse events have occurred during post-marketing experience. The most commonly reported events in children were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%).[10] [[Table 5]]
Dosage and Administration
As per Expert Consensus on The Management of Dermatophytosis in India (ECTODERM India), systemic antifungals like fluconazole (150mg-300mg/week) can be used, when other oral antifungals such as terbinafine or itraconazole have failed. [1]
According to the experts from Indian Association of Dermatologists, Venereologists and Leprologists (IADVL) Task Force against Recalcitrant Tinea (ITART), patients with the first episode, with no prior history of treatment may be prescribed tablet fluconazole 150 mg thrice weekly. [6]
Fluconazole in a dose of 150 mg thrice weekly for 8 weeks seem to lead to a good clinical outcome in patients with recalcitrant dermatophytosis. [20] [[Table 6]]
Place of Fluconazole in the Treatment of Dermatophytosis
Though, Itraconazole or Terbinafine is first line of treatment, Fluconazole is the alternative first choice of systemic drug when prolonged duration of treatment is required. According to the experts from the IADVL Task Force against Recalcitrant Tinea (ITART), fluconazole needs to be taken for a longer duration than Itraconazole or Terbinafine for the management of glabrous tinea. [6] Regarding treatment duration, antifungal agents should be prescribed for 2 more weeks post clinical cure, in accordance with current scenario of dermatophytosis in India. [1] According to American Family Physician (AFP) guidelines, oral fluconazole is acceptable treatment for tinea capitis, with shorter treatment courses than griseofulvin (Evidence rating A). [21] [[Table 7] ]
Conclusion
India has been observing an increase in the prevalence of superficial fungal infections and it has become clinically challenging to treat recalcitrant dermatophytosis due to newer isolates, antifungal resistance, patient non-compliance, changing pathophysiology and symptoms. Compiled data on guideline recommendations, efficacy, safety, pharmacokinetic advantages will help dermatologists and general physicians in clinical decision making to prescribe oral fluconazole in the management of tinea corporis, tinea cruris and tinea pedis. Fluconazole offers better safety and can be prescribed for a longer duration in patients with recalcitrant dermatophytosis.
Conflict of Interest
None.
Source of Funding
None.
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