Sign In or Register
Username:
Password:
Don't have
an account?
REGISTER NOW!
It takes only a moment.

DERMATOLOGY

FUNGAL INFECTIONS OF THE SKIN AND SKIN STRUCTURES

 

© 2004- DoctorFungus

 

 

 

INTRODUCTION

 

The clinical nomenclature for the fungal infections of the hair, nail, skin, and subcutaneous tissues is often confusing upon first en- counter. The terms overlap, some of the terms sound like names of fungi (but aren’t), and different definitions may be encountered in different texts. A general overview to this area is found below, and it provides one consistent scheme for thinking about this area. As you read it, it is helpful to understand these terms:

 

1. Phaeohyphomycosis: Used for infections due to melanin-producing, or dematiaceous, species of moulds. Melanin is a black pigment, and fungi that produce melanin are visible black or brown. The term applies to fungal structures in tissue or clinical specimens whether or not the melanin is visible without special stains. The Fontana-Masson stain is used to identify melanin in the cell walls of the fungus. The actual morphology in the tissue may consist of any combination of hyphae, pseudohyphae, or yeast cells of the infection causing fungus. A detailed discussion on Phaeohyphomycosis and its subtypes is also available.

 

2. Hyalohyphomycosis: This term parallels phaeohyphomycosis, but is used for infections due to NON-melanin-producing, or non-dematiaceous, species of moulds.

 

3. Dermatophyte: This term refers to three specific genera of fungi: Epidermophyton, Trichophyton, and Microsporum. These three genera have an especially strong association with fungal infections of the skin, hair, and nails. Indeed, the association has historically been so strong that diseases due to these three genera have often been given their own names, even though clinically identical diseases might be caused by fungi of other genera.

 

FORMS OF THE DISEASE

The syndromes discussed here are:

- Dermatophytosis

- Dermatomycosis

- Onychomycosis

- Piedra

- Mycetoma

- Lobomycosis

- Miscellaneous/other Syndromes

 

Dermatophytosis

The classic skin and hair infections that characterize the focus of much of medical dermatology are grouped here. There are three genera of moulds that contain the dermatophytosis-causing species. These are Epidermophyton, Trichophyton, and Microsporum.

The characteristic features of a dermatophyte mould are:

1. It belongs to one of the three genera listed above,

2. It is keratinophilic (which is to say that it can grow on keratin), and

3. It can do so on a living host.

There are fungi which are keratinophilic, but which don’t grown on the living host. For example, Chrysosporium indicum or C. keratinophilum will grow on keratin, but only if the keratin is completely separate from the host. Feathers, animal hooves, hair, and animal skin all can be used as substrates for the keratinophilic fungi. In fact, these types of materials are used to isolate keratin from soil and other environments where this group of fungi grow.

The dermatophytes as a group are special because of their history and medical importance. They are the agents that are associated with the “tineas,” a series of named diseases that use Latin binomials for their naming structure. These binomials can sound like names of fungi, but aren’t. For example, Tinea capitis is the general term for dermatophytic infection of the scalp. These dis- eases are as shown in the list and are discussed in detail on their respective pages:

- Tinea capitis

- Tinea favosa

- Tinea corporis

- Tinea pedis

- Tinea manuum

- Tinea imbricata

- Tinea cruris

- Tinea barbae

- Tinea nigra

- Tinea ungium

 

Dermatomycosis

The organisms that cause dermatomycosis produce infections of the skin and hair that in many ways parallel those caused by the dermatophytes. A wide variety of yeasts and moulds can produce infection. For example, one might see:

1. A Tinea pedis-like infection due to Scytalidium dimidiatum

2. A Tinea barbae-like infection due to Geotrichum candidum

 

Note that we do not usually use the word Tinea to describe these infections, as those terms are generally restricted to disease produced by the dermatophytes. There are, of course, exceptions to this rule.

The first exception is Tinea versicolor. Correctly known as Pityriasis versicolor, this is a distinctive syndrome in which yellow-to- brown lesions appear on the chest, trunk, or abdomen. The name versicolor comes from the range of colors that are seen. This infection is due to Malassezia furfur.

Another exception is Tinea nigra. This refers to a dark-colored superficial infection of the stratum corneum by a dematiaceous fungus called Hortaea werneckii. The palms are the most commonly involved site, but any glabrous region may be involved. Thus, this syndrome could be said to be Tinea manuum- or Tinea corporis-like. This infection occurs in people who contact salt and salty water. The fungus has a high tolerance for salt.

 

Onychomycosis

Similar to the idea of dermatomycosis as a parallel to the dermatophytosis, infections of the nail are so important that they get their own name. The term Onychomycosis is used both to refer to non-dermatophyte nail infections or to any fungal nail infection caused by any fungus. The term Tinea unguium can be applied only if the infection is due to a dermatophyte. However, the distinction is narrow, technical, and with not much clinical value. The leading non-dermatophyte mould cause of onychomycosis is Scopulariopsis brevicaulis. The leading yeast cause of onychomycosis is Candida albicans. It is not uncommon to have more than one fungus species jointly causing the infection.

 

Piedra

Piedra refers to colonization of the hair shaft that results in firm, irregular nodules. If the nodule is dark, the infection is Black Piedra and is due to Piedraia hortae. These nodules will be firmly adherent to the shaft and cannot be readily detached. The nod- ule is the ascomycete fruiting body of the fungus, know as an ascostroma. If the nodule is white, the infection is White Piedra and is due to Trichosporon beigelii. These nodules are a loose aggregate of hyphae and arthroconidia. They are easily detached from the hair shaft by rubbing along its length.

 

Mycetoma

Mycetoma and chromoblastomycosis are loosely related syndromes along a spectrum of invasion of the subcutaneous tissue. They thus differ fundamentally from all of the above forms of fungal infection due to their greater depth of tissue invasion. Mycetoma is characterized by tissue swelling, draining sinuses, and the release of sclerotia (also known as granules or grains) from these draining sinuses. Dematiaceous or non-dematiaceous fungi may cause the infection. This results in different colors of the sclerotia and can be helpful in the identification of the causal agent. This disease is typically chronic and may result in amputa- tion of the infected body part. On pathological examination, one sees masses of aggregated hyphae and associated host tissue response. The architecture or pattern of the aggregated hyphae in the sclerotium can be used to help identify the causal agent.

 

Chromoblastomycosis

Chromoblastomycosis is an infection involving the cutaneous and subcutaneous tissue. A key pathological requirement is for the production of muriform cells, or cells that contain both horizontal and vertical dividing walls. Such infections are always due to melanin producing, dematiaceous fungi such as Fonsecaea pedrosoi. This disease may also be chronic, but amputation is never necessary. If one sees subcutaneous infection by a mould, but without the formation of muriform cells, the general terms phaeohyphomycosis or hyalohyphomycosis are employed depending on the melanin-producing character of the fungus. Note the subtle difference here in terms of causative agents: chromoblastomycosis is always caused by melanin producing fungi.

 

Lobomycosis

Lobomycosis is an uncommon, except in some highly geographically restricted areas, cutaneous and subcutaneous infection caused by an organism that is called Lacazia loboi. The fungus is unique in that it has never been cultured. Based upon molecula based information, the fungus is an ascomycete.

 

Other

Basidiobolus, Conidiobolus, and Sporothrix can also cause indolent skin structure infections. Likewise, Candida causes skin structure infections.

Besides, several systemic fungal infections can invade the skin and cause more or less characteristic skin lesions as part of their clinical pictures. They include endemic mycosis (histoplasmosis, coccidioidomycosis, and blastomycosis) and opportunistic fungal infections (invasive candidiasis, aspergillosis, and zygomycosis).

 

WHAT IS DERMATOLOGICAL MYCOSIS

 

The dermatological mycoses include some very common infections such as the tineas and pityriasis versicolor. Their prevalence varies in different parts of the world but in many tropical countries they are the most common causes of skin disease and their incidence is increasing steadily.

Three genera of pathogenic dermatophyte fungi – Trichophyton, Microsporum and Epidermophyton are responsible for most of these common conditions. Candida species, typically C. albicans, are also important dermatological pathogens, as they cause cutaneous candidiasis.

The impact of dermatological mycoses on the lives of patients can be quite significant, for example, Tinea pedis (‘athlete’s foot’) is infectious and can have a notable impact on large institutions, such as schools, the army, and industry.

Onychomycosis can cause pain, difficulty in wearing shoes and, at worst, inability to walk. In other words, patients affected with dermatological myosis may find it difficult to work.

 

FLUCONAZOLE AS AN EXAMPLE FOR ORAL THERAPY

 

Fluconazole is a broad-spectrum bis-triazole agent which is a highly selective inhibitor of fungal cytochrome P450-mediated lanosterol [14C] demethylase, preventing the conversion of lanosterol to ergosterol. This results in a deficiency in the major lipid of the fungal cell membrane and leads to inhibition of fungal cell growth. Fluconazole, however, has negligible effects on mammalian P450 enzymes involved in the synthesis of cholesterol, adrenal corticosteroids, testoterone and estrogen.

Fluconazole can be used for the treatment of a wide range of fungal infections, including vaginal and other mucosal candidiasis, systemic candidiasis, cryptococcosis, and dermatological mycoses including cutaneous candidiasis, tineas and onychomycosis.

 

The doses most studied and used for the treatment of dermatological mycoses are 50 mg once-daily and 150 mg once-weekly. Fluconazole, administered either once-daily or once-weekly, is effective in the management of dermatomycoses due to Candida species or dermatophyte fungi, such as Trichophyton, Microsporum or Epidermophyton genus.

 

Safety data from patients treated with either once-daily or once-weekly fluconazole in dermal studies, showed the drug to be very well tolerated. In the once-daily studies, the most common side-effects were headache (3.1%), abdominal pain (2.3%), and nau-sea (1.6%). Abdominal pain, acne, and dyspepsia (1.8% each) were the most frequently reported side-effects in the once-weekly studies.

 

TISSUE CONCENTARTIONS

Fluconazole is highly soluble in water, well absorbed after oral administration (oral bioavailability is over 90% and is unaffected by food intake), shows a low affinity for protein binding, is predominantly excreted unchanged in the urine, has a long half-life, and has a high affinity for dermal tissues.

The uptake of fluconazole by the skin, nails and hair has been investigated in a study in healthy volunteers. The highest levels of fluconazole were observed in the stratum corneum, reaching 38 mg/g on the 150 mg once-weekly dose, representing a 12-fold accumulation compared with plasma levels. Fluconazole was eliminated from the skin more slowly than from plasma, being detectable 2 months after the last dose in the stratum corneum.

 

RESULTSOF CLINICALSTUDIES

The following results were concluded as follows:

 

Overall efficacy in tineas and cutaneous candidiasis

* Once-weekly administration of fluconazole was as effective and well-tolerated as once-daily ketoconazole.

* Clinical success rates of 94% for fluconazole and 96% for ketoconazole, and mycological eradication rates of 93% and 91%, respectively were observed at the end of treatment.

* At long-term follow-up, clinical success rates were 84% and 83% for patients treated with fluconazole and ketoconazole, respectively. Mycological relapse was uncommon with either treatment (12% for fluconazole versus 16% for ketoconazole).

*Fluconazole had equivalent clinical and mycological efficacy to ketoconazole, but with the advantage of once-weekly oral administration, which may improve patient compliance to therapy.

 

A multicenter study, designed to assess the efficacy and safety of once-weekly 150 mg fluconazole in treating adult patients with tinea (corporis, cruris, pedis) or dermal Candida infections.

* Patients were treated for an average of 4.6 weeks.

* Clinical success (cure + improvement) was reported for 96% of lesions at the end of treatment, and 92% at long-term follow-up .

* Mycological eradication occurred in 92% of lesions at the end of treatment, and 89% at long-term follow-up.

* 5% of the patients experienced adverse events. Of these patients, only 1% discontinued treatment.

* 93% of patients preferred once-weekly oral fluconazole to their previous topical therapy .

As a part of this multicenter study, a subgroup was studied to investigate the efficacy of once-weekly fluconazole (150 mg) in specific infections.

 

Tinea corporis:

* A total of 85 evaluable patients (52 with tinea corporis alone, 33 also having tinea cruris and/or tinea pedis) were treated with once-weekly 150 mg fluconazole therapy for an average of 4.4 weeks (range 2–8 weeks).

* At the end of treatment, 75% of lesions were clinically cured and 22% had improved, giving an overall clinical success rate of 97%.

* Clinical success was maintained at the long-term follow-up visit (95%), with a relapse rate of only 5%.

 

Tinea cruris:

* A total of 132 patients (88 with tinea cruris alone, 44 also having tinea pedis, tinea corporis or cutaneous candidiasis) received treatment with fluconazole for an average of 4 weeks (range 2–8 weeks).

* At the end of treatment, 84% of lesions were clinically cured and 16% had improved, giving an overall clinical success rate of 100%.

* Clinical success was maintained at the long-term follow-up visit, with a failure rate of only 1% and a relapse rate of 8% .

 

Cutaneous candidiasis:

* A total of 44 patients (42 with cutaneous candidiasis alone, two also having tinea pedis) received fluconazole therapy for an average of 5 weeks (range 3–8 weeks).

* In all, 66% of lesions were clinically cured and 30% were improved at the end of treatment, giving an overall clinical success rate of 96%.

* Clinical success was maintained at the long-term follow-up visit, with failure and relapse rates of only 3% each.

 

An open, multicenter study investigated the efficacy of 1–4 once-weekly doses of 150 mg fluconazole in the treatment of dermatophytosis (tinea cruris, tinea corporis) and cutaneous candidiasis in 95 patients (age 16–60 years).

* A total of 4/95 (4%) patients required one dose, 43/95 (45%) required two doses, 36/95 (38%) required three doses, 11/95 (12%) required four doses and one patient (1%) took five doses. Three patients were excluded from the clinical efficacy analysis because of an uncertain diagnosis, failure to return for follow-up or concurrent infection with ectoparasites.

At long-term follow-up, clinical cure was maintained in 80/91 (88%) of patients.

* Mycological evidence of infection was present in only 1/86 (1%) patients at the end of treatment.

In another open, non-comparative study, 115 patients with tinea cruris and/or tinea corporis were treated with fluconazole 150 mg once-weekly for 2–4 weeks.

* Mean severity scores (based on severity of pruritus, erythema, scaling, burning/pain and vesiculation) decreased significantly from 7.1 at baseline to 1.5 at end of treatment (P=0.001).

* Of evaluable patients, clinical success was reported in 95% (51% cured, 44% improved) 1 week after the last dose and in 94% (87% cured, 7% improved) 3 weeks after the last dose.

* At follow-up (3 weeks after last dose), mycological eradication as determined by culture, occurred in 89% of evaluable patients.

Microscopy indicated a mycological eradication rate of 93%.

 

Tinea pedis

The efficacy of oral fluconazole (150 mg once-weekly) was investigated in an open, non-comparative study of adult patients (age 18–65 years) with tinea pedis. A maximum of four doses of fluconazole were given.

* Patients with Candida infections required fewer doses (mean 1.8) than those infected with other organisms (mean 3.3 for Trichophyton rubrum infection, for example).

* Clinical cure was obtained in 74% evaluable patients at the end of treatment, with 25% patients substantially improved, giving a clinical success rate of 99%. Only one patient failed clinically.

* At long-term follow-up, 28–30 days after the last dose, the clinical success rate remained high: 77% patients were clinically cured and 22% were improved .

* Mycological eradication occurred in 87% of patients post-treatment.

In the non-comparative study, 223 patients with tinea pedis (with or without other tineas or cutaneous candidiasis) received 150 mg fluconazole once-weekly for 3–7 weeks (mean duration 5.1 weeks).

* At the end of treatment, the clinical success rate for tinea pedis lesions was 94%

* At follow-up (4–6 weeks after the last dose), the clinical success rate was 91%.

 

Onychomycosis

In an open, non-comparative study, 74 adult out-patients (age 18–65) with severe onychomycosis were treated with fluconazole (150 mg once-weekly) for 3–12 months. In all cases, infection had been present for more than 1 year, and 40% of patients had suffered from onychomycosis for at least 5 years.

* Fluconazole therapy produced either cure or improvement at the end of treatment in 97% of patients.

* At a follow-up visit 6 months after the end of treatment, 87% of patients achieved clinical success (cure + improvement).

* The mycological response to fluconazole was excellent: the pathogen was eradicated in 81% of patients at the end of treatment and 79% at follow-up.

Some smaller studies and case reports also support the use of fluconazole in the treatment of onychomycosis. A case of onychomycosis in an immunosuppressed renal transplant patient, was reported as successfully treated with once-weekly 150 mg fluconazole after 5 months.

Two other cases in which 100 mg fluconazole, in one case given every other day, in the other given once-daily for 2 weeks, then every other day, were reported as successful after long-term treatment (at least 8 months).

A non-comparative study of 16 subjects was conducted, in which the efficacy of once-daily 100 mg fluconazole was established. All patients demonstrated clinical improvement after 6 months of therapy.

 

Pityriasis versicolor

Patients with mycologically-proven pityriasis versicolor were treated with either fluconazole 150 mg once-weekly; fluconazole 300 mg once-weekly; or fluconazole 300 mg repeated after 2 weeks if necessary. Treatment was continued for up to 4 weeks; clinical and mycological assessments were made at the end of treatment and at follow-up 4 weeks later.

* Results showed a 95% clinical success rate for fluconazole, with a mycological eradication rate of 86%.

* Cure rates were above 70% in all three groups. Patients receiving 300 mg/week had the highest cure rate followed by those receiving 300 mg repeated after 2 weeks if necessary.

An open, randomized, multicenter, comparative trial, in which 194 adult patients (>16 years) with mycologically-proven pityriasis versicolor were enrolled. A total of 194 patients received fluconazole (300 mg once-weekly for 2 weeks, repeated after 1 week, if necessary); 73 patients received itraconazole (200 mg/day for 7 days); 85 patients were given ketoconazole (200 mg/day for 14 days); and 35 patients received topical clotrimazole (twice-daily for 21 days). Clinical and mycological assessments were performed at baseline, end of treatment and at a 60-day follow-up.

* There were no significant differences between treatment groups in clinical responses at follow-up.

* Over 90% of patients showed clinical success (cure + improvement) at Day 14, and high response rates were sustained at subsequent visits.

* The relapse rate at follow-up for fluconazole (6.3%) was lower than that of itraconazole (15.3%), indicating that while the mycological effect of fluconazole is delayed, it may be maintained for longer than that of some other antifungal agents.

 

DOSAGE

- dermatomycosis: (Tinea capitis, Tinea favosa, Tinea corporis, Tinea pedis, Tinea manuum, Tinea imbricata, Tinea cruris, Tinea barbae, Tinea nigra, Tinea ungium): 50mg /day or 150 mg /week

- blastomycosis: 400- 800 mg/kg if itraconazole is not absorbed or ketoconazole not tolerated (in non-immunocompromised patients)

- oropharyngeal candidosis, 50 - 100 mg, once daily for 1–2 weeks, or 3 mg/kg, or 3 mg/kg, two divided doses in children

- esophageal and mucocutaneous candidosis, 50 - 100 mg per day for 2– 4 weeks

- lower urinary tract candidosis, 200 mg per day for 7 -14 days

- candidemia,

non-neutropenic: 400 mg loading dose, followed by 200 - 400 mg per day for 2 weeks

Candida lusitania infection: 400 mg per day.

- disseminated candida,

acute: 400 - 800 mg/day or higher in less critically ill patients

chronic: 200 - 400 mg /day in stable patients

- candida meningitis 400- 800 mg /day

- candida carditis 400- 800 mg/day

- candida endophthalmitis 400-800 mg/day for 6 -12 weeks following amphotericin plus flutocytosine

- coccidioidomycosis

pulmonary cavity or fibronodular: 400 mg/day for 6- 12 months

slowly progressive pulmonary: 400-800 mg/day

meningitis: 600 - 800 mg/day

HIV-infected: 400 mg /day life-long following infection control

- cryptococcosis

Meningitis in normal hosts: 200–400 mg per day for a mininmum of 10 weeks, then 10 months maintenance.

Pulmonary, symptomatic infection in normal hosts: 200 - 400 mg/day for 3 - 6 months

Extra-pilmonary, non meningeal: 400 mg/day for 3 – months meningitis in AIDS patients: initial therapy with amphotericin B plus flutycosine for 2 -3 weeks, then fluconazole 400 mg/day for 10 weeks, then fluconazole 200 mg/day for life

- paracoccidioidomycosis

oral or parenteral 200-400 mg per day for 6 months

- use in renal impairment

Fluconazole is excreted predominantly in the urine as unchanged drug — no adjustments in single dose therapy are required; in patients with impaired renal function who will receive multiple doses of fluconazole, the normal recommended dose (according to indication) should be given on day 1, followed by a daily dose based on the following information:

- for creatinine clearance >50 ml/min, use 100% recommended dose

- for creatinine clearance 11–50 ml/min, use 50% recommended dose

- for patients receiving regular dialysis, use one dose after each session

- prophylaxis for candidosis, 50–400 mg per day; use 400 mg per day in high-risk patients several days before anticipated neutropenia, and continue for 1 week after recovery of neutrophil count to 1-109/l

- children

- mucosal candidosis, 3 mg/kg per day

- systemic candidosis and cryptococcosis, 6–12 mg/kg per day

- prophylaxis, 3–12 mg/kg per day

 

SUMMARY

* Dermatological mycoses are very common and can have a significant impact on patients’ quality of life.

* Fluconazole achieves sustained high levels in dermal tissues following oral dosing and can be given either 50 mg once-daily or

in a unique 150 mg once-weekly regimen for the treatment of dermatological mycoses.

* Patients have been shown to prefer once-weekly oral fluconazole to topical therapies for the treatment of tinea corporis, tinea

cruris, tinea pedis and cutaneous candidiasis.

* Fluconazole, given once-weekly at a dose of 150 mg, is highly effective in the treatment of onychomycosis.

* In the treatment of pityriasis versicolor, once-weekly fluconazole is as effective as ketoconazole, itraconazole or topical clotrima-

zole given on daily bases.

* Dermal studies in 976 subjects show that fluconazole is well tolerated and has an excellent safety profile in both once-daily and once-weekly regimens.

 

 

« Previous:
DENTISTRY
Next:
EAR, NOSE AND THROAT MEDICINE »