Fungal infections

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42 Fungal infections

M. Narayanan

Key points

• Fluconazole, a triazole, is considered to be standard therapy for oropharyngeal, oesophageal and vaginal candidiasis.
• Itraconazole and terbinafine are efficacious, non-toxic alternatives to griseofulvin when systemic treatment of dermatophytosis is required.
• Fungi can cause overwhelming deep-seated or systemic infections in immunocompromised hosts that are refractory to antifungal treatment alone.
• Incidence of non-Aspergillus mould infections has increased in transplant recipients over the past decade, and these can be lethal.
• Most therapy for deep-seated fungal infection in the immunocompromised host is empirical due to the difficulties in reaching a rapid, accurate diagnosis of systemic fungal infection.
• Lipid-complexed formulations of amphotericin offer a less toxic alternative to conventional amphotericin in the treatment of systemic fungal infection.
• Voriconazole, a triazole, appears to be an effective alternative to amphotericin in the treatment of invasive aspergillosis.
• Caspofungin is an alternative agent to amphotericin for invasive aspergillosis and may have a role to play in the empirical treatment of febrile neutropenic patients.

Fungi are ubiquitous microorganisms that differ from bacteria in their cellular structure, and this makes them naturally resistant to antibacterial agents (Table 42.1). Fungi are broadly divided into yeasts and moulds. Yeasts are typically round or oval shaped microscopically, grow flat round colonies on culture plates and reproduce by forming buds from their cells. Moulds (e.g. Aspergillus, Mucor) appear as a collection or mass (mycelium) of individual tubular structures called hyphae that grow by branching and longitudinal extension. They appear as a fuzzy growth on appropriate conducive medium (e.g. Penicillium colonies on stale bread or Sabourauds agar). The most commonly seen yeast, Candida, occasionally produces pseudohyphae.

Table 42.1 Important characteristics of a fungal cell

Fungi Bacteria
Eukaryotes Prokaryotes, eubacteria
Cell and cytoplasm Cell and cytoplasm
Nucleus with multiple chromosomes enclosed in a nuclear membrane No nucleus or nuclear membrane, has single chromosome
Contains endoplasmic reticulum, golgi apparatus, mitochondria and ribosomes Other structures absent except ribosomes
Cytoplasmic membrane Cytoplasmic membrane
Contains phospholipids and sterols Contains phospholipids and no sterols
Cell wall Cell wall
Contains chitins, mannans,+/- cellulose Contains peptidoglycan, lipids and proteins

There are hundreds of species of fungi found in the environment, but only the important human fungal pathogens and their treatment will be discussed in this chapter. The fungi of medical importance can be divided into four groups (Table 42.2).

Table 42.2 Classification of fungi of medical importance

Group Examples Infections caused
Yeast Candida spp. Oral and vaginal thrush
Deep seated: candidaemia, empyema
Cryptococcus neoformans Meningitis
Saccharomyces cervesiae Rare systemic infection in immunocompromised host
Malassezia furfur
Yeast-like Geotrichium candidium  
Trichosporon beigelii
Dimorphic fungi Blastomyces dermatitidis For first three: deep systemic organ involvement, more commonly in the immunocompromised host
Coccidioides immitis Deep subcutaneous infection following trauma
Histoplasma capsulatum
Paracoccidioides brasiliensis
Sporothrix schenckii
Moulds
1. Hyaline    
a. Zygomyces Rhizopus Infections in neutropenic patients and those with diabetic ketoacidosis
Mucor
Absidia
b. Hyalohyphomycosis Aspergillus fumigatus and other Aspergillus spp. Systemic infection: invasive pulmonary or central nervous system involvement
Fusarium Fusarium keratitis
Scedosporium apiospermum Deep infection in immunocompromised host, for example, transplant patients
2. Dermatophytes Trichophyton spp. For all three: various skin (ringworm) hair and nail infections
Microsporum spp.
Epidermophyton
3. Dematiaceous Alternaria spp. Deep tissue infection with granulomas
Cladophialora spp. Chromomycosis, mycetomas

Some fungi like Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis are known as dimorphic fungi (Table 42.2) because they are found in the infected host in yeast form at 35–37 °C temperature but grow as moulds, in vitro, at room temperatures (22 °C incubation).

Fungi mainly reproduce by forming spores through mitosis giving rise to two daughter cells. They are known by names given to this imperfect state (asexual reproduction), but the same fungus, for example, Scedosporium apiospermum (asexual form) is also known as Pseudoallescheria boydii (sexual form). However, for all practical purposes, only the oldest and best-established name for the fungi is used in diagnostic laboratories.

Fungal spore are spread by air, water and direct contact with infected source. Humans usually become infected by inhalation of airborne spores or by inoculation into traumatised skin and mucous membrane.

Laboratory diagnosis

Microscopical examination and culture of fungi is the mainstay of laboratory diagnosis. Appropriate staining of histological sections of affected tissue is helpful in making a diagnosis when culture growth may or may not be positive. Yeast colonies and moulds are characteristic in their appearance on culture plates and can be preliminarily identified by their shape, colour and temperatures at which they grow. For the genus and species identification of yeasts, microscopic examination and biochemical tests are necessary. Moulds are identified by their morphology and the nature of sporulation on agar medium.

Antifungal sensitivity testing for yeast is done by determining the minimum inhibitory concentration (MIC) of the antifungal agent in the E test® strip method which has now replaced the measurement of ‘inhibition zone’ by disc testing. E-test® strips are also available for determining sensitivity of antifungal agents against moulds. Molecular diagnosis utilising polymerase chain reaction (PCR) is not available for use in routine practice. Serological diagnosis to look for antibodies in patient’s blood is of use only in Coccidioides infection. Enzyme-linked immunosorbent assay (ELISA) methods to look for galactomannan antigen in deep Aspergillus infection are available but not fully evaluated. A positive test needs to be interpreted in conjunction with other findings. Antigen detection is useful in disseminated Histoplasmosis and Cryptococcosis.

Fungal infection

It is important to distinguish harmless colonisation with fungi and significant infection, as only the latter would benefit from antifungal treatment.

More often, fungi are a cause of superficial infections of the skin and mucous membranes.

In some susceptible hosts whose immune system is heavily compromised, deep-seated infections involving organs like lungs and brain can manifest as ‘difficult to cure’ infections, for example, pulmonary aspergillosis or cryptococcal meningitis.

Antifungal agents

Topical and systemic antifungal agents are available to treat mucocutaneous candidiasis, various forms of tinea (ringworm) and other dermatophytosis, onychomycosis and deep-seated systemic infections (e.g. candidaemia, mucor mycoses, fungal endocarditis, osteomyelitis). Some infective conditions and their treatment are dealt with in the sections that follow. The side effects of a range of antifungal agents are set out in Table 42.3.

Table 42.3 Side effects of antifungal agents

Drug Side effects
Griseofulvin Mild: headache, gastro-intestinal side effects. Hypersensitivity reactions such as skin rashes, including photosensitivity
Moderate: exacerbation of acute intermittent porphyria; rarely, precipitation of systemic lupus erythematosus. Contraindicated in both acute porphyria, systemic lupus erythematosus, pregnancy and severe liver disease
Terbinafine Usually mild: nausea, abdominal pain; allergic skin reactions; loss and disturbance of sense of taste. Not recommended in patients with liver disease
Amphotericin Immediate reactions (during infusion) include headache, pyrexia, rigors, nausea, vomiting, hypotension; occasionally, there can be severe thrombophlebitis after the infusion
Nephrotoxicity and hypokalaemia
Anaemia due to reduced erythropoiesis
Peripheral neuropathy (rare)
Cardiac failure (exacerbated by hypokalaemia due to nephrotoxicity)
Immunomodulation (the drug can both enhance and inhibit some immunological functions)
Flucytosine Mild: gastro-intestinal side effects (nausea, vomiting). Occasional skin rashes
Moderate: myelosuppression (dose related), hepatotoxicity
Fluconazole Mild: nausea, vomiting and occasional skin rashes; occasionally, elevated liver enzymes (reversible)
Moderate or severe: rarely, hepatotoxicity and severe cutaneous reactions, especially in AIDS patients
Itraconazole Mild: nausea and abdominal pain; occasional skin rashes
Moderate or severe: rarely, hepatotoxicity
Voriconazole Similar to fluconazole and itraconazole
Mild: reversible visual disturbances occur in about 30% patients
Caspofungin Mild: gastro-intestinal side effects; occasional skin rashes

Superficial infection

Candida infections

Epidemiology

Candida is a normal commensal of the human gastro-intestinal tract and skin. Loss of skin and mucosal integrity or use of broad-spectrum antibiotics which alter normal bacterial flora allow overgrowth of endogenous Candida. There are more than 100 species of Candida, but only a few are important as common human pathogens.

Thrush is candidal infection of the mucous membrane. It can manifest as oral infection, for example, oral thrush in various patient groups, vulvo vaginal thrush in females, balanitis in the uncircumcised man or intertrigo infection in moist skin surfaces in close proximity, for example, groin area. Patients with diabetes and steroid users, whether inhaled or oral, are also prone to infections. Dysphagia due to candidal oesophagitis presents in patients with AIDS and cancer.

Clinical presentation

Oral thrush typically presents as a sore mouth with white curd like patches on the tongue or oral mucosa which can bleed on scraping. Females with vaginal thrush present with itching and a creamy vaginal discharge. Skin infection in babies can present as pustular body rash or nappy rash in the moist perianal area. Candida folliculitis may present in unkempt, bearded men. Nail infection with Candida (onychomycosis), or subcutaneous tissue involvement under the nail (paronychia) is seen in people whose occupation involves prolonged hand immersion in water.

In severe oesophageal candidiasis, ulceration or formation of pseudomembranes and, rarely, perforation of lower third of the oesophagus may occur.

Candida can be a cause of hospital-acquired infection in patients as it is found in the hospital environment on inanimate objects or on skin of health care workers.

Treatment

Oral and vaginal candidiasis may be treated by either topical or systemic antifungal agents. The drugs currently available for topical use fall into two groups: the polyenes, of which only amphotericin and nystatin are used clinically, and the imidazoles such as econazole, clotrimazole, miconazole and fenticonazole. These agents are essentially identical in their antifungal activity and the only reasons to choose between them are price and differing preparations. The two systemic agents are both triazoles (fluconazole and itraconazole) and can be given by mouth. Skin infections may also be treated topically, but nail infections are unlikely to respond to a topical antifungal agent alone and require systemic treatment. Oesophagitis will invariably require systemic treatment.

Topical treatment

The polyenes are broad-spectrum antifungal agents that are virtually insoluble in water and which are not absorbed from the gastro-intestinal tract or from skin or mucous membranes. Both nystatin and amphotericin (but particularly nystatin) are available in a wide range of formulations including pessaries, creams, gels, tablets, pastilles, etc. The choice of formulation clearly depends on the site of infection and patient preference.

Systemic treatment

Three triazole agents: fluconazole, itraconazole and voriconazole are available for systemic treatment of oral and vulvo vaginal candidiasis (VVC). A good source of advice on treatment is that from the Infectious Diseases Society of America (Pappas et al., 2009):

Vulvo vaginal candidiasis

• Several topical antifungal agents provide effective therapy; no agent is clearly superior
• A single 150-mg dose of fluconazole is recommended for the treatment of uncomplicated cases
• For recurring vulvo vaginal candidiasis, 10–14 days of induction therapy with a topical or oral azole, followed by fluconazole at a dosage of 150 mg once per week for 6 months, is recommended
• Complicated vulvo vaginal candidiasis requires topical therapy for 7 days or multiple doses of fluconazole (150 mg every 72 h for 3 doses). Recurrent infections with non-albicans Candida, for example, C. glabrata, may be more difficult to treat.

Candida balanitis

• Candida balanitis can be treated with topical polyenes or imidazoles, or with systemic fluconazole in the same dose as for vaginal infection.

It is sometimes stated that when treating a woman with vaginal candidiasis, the male partner should be treated simultaneously to prevent reinfection. Although there is no evidence to support this approach, it may be considered in women who suffer from repeated vaginal candidiasis.

Guidance on the treatment of topical and systemic therapy (Pappas et al., 2009) are also available for treatment of mild, moderate and severe oropharyngeal and oesophageal candidiasis and suppressive therapy for patients with HIV infection.

Dermatophytosis

Epidemiology

Dermatophytosis, or tinea, is a condition caused by three genera of dermatophyte fungi: Trichophyton, Epidermophyton and Microsporum. Unlike Candida, these are moulds which have a predilection for keratinised tissue such as skin, nail and hair. These fungi are very widely distributed throughout the world and may be acquired from the soil (anthrophilic, e.g. Trichophyton rubrum), from animals (zoophilic) or from humans (geophilic) infected with the fungus.

Some species are prevalent throughout the world, for example, Microsporum canis, while some are area specific, for example, Trichophyton mentagrophyte in Europe and New Zealand.

Clinical presentation

The classical clinical presentation of dermatophyte infection of the skin is ringworm (tinea), a circular, inflamed lesion with a raised edge and associated skin scaling. However, presentation is influenced by the site of infection, for example, tinea pedis (athlete’s foot) between the toes, tinea cruris on the body, and by the actual species of fungus causing the infection. In general, less severe lesions are produced by human fungal strains, while those acquired from animals can produce quite intense inflammatory reactions.

Dermatophytosis of the nail results in thickened, discoloured nails, while in the scalp, infection presents with itching, skin scaling and inflammation, and patchy hair loss (alopecia).

Rarely, deep dermatophytosis may be seen in immunocompromised patients with involvement of subcutaneous tissue (granuloma).

Diagnosis

The diagnosis of dermatophyte infection is confirmed by collecting appropriate specimens such as material from infected nails and skin. The fungi can be seen microscopically and specimens may also be cultured, but antifungal susceptibility testing is not required.

Treatment

Small or medium areas of skin infection can be treated with topical therapy, but nail, hair and widespread skin infection should be systemically treated with oral antifungal agents.

The most commonly used topical agents are the imidazoles, of which a wide variety is available, including clotrimazole, ecoazole, miconazole, sulconazole and tioconazole. There is little to choose between these agents, all of which are usually applied two or three times daily, continuing for up to 2 weeks after the lesions have healed. Side effects are uncommon and usually consist of mild skin irritation. Other topical agents include amorolfine, terbinafine and tolnaftate.

The main oral antifungals used for dermatophytosis are terbinafine, itraconazole and fluconazole. Griseofulvin is an alternative treatment for tinea capitis.

Terbinafine

Terbinafine was the first member of a new class of antifungal agents, the allylamines, which became available for systemic use. These agents act by inhibition of the fungal enzyme squalene epoxidase, an enzyme involved in the synthesis of ergosterol, an essential component of the fungal cytoplasmic membrane. Although terbinafine has a very broad antifungal spectrum in the laboratory, its in vivo efficacy does not correspond to its in vitro activity, and it is used only for the treatment of dermatophyte infection.

Terbinafine is the treatment of choice for tinea infections at 250 mg/day for 2–4 weeks, 250 mg/day for 6 weeks for fingernail infection and 12 weeks for toenail infection.

About 70% of an oral dose of terbinafine is absorbed, and the drug appears in high concentrations in the skin. The half-life is about 16–17 h, and therefore the drug can be given once per day. Terbinafine is metabolised in the liver and the metabolites are excreted in the urine so that hepatic or renal dysfunction will prolong the elimination half-life.

Itraconazole is the second preferred agent at 200 mg/day for 1–2 weeks and longer, with repeated courses for finger and toenail involvement.

Griseofulvin

The first orally administered treatment for dermatophytosis was griseofulvin, which has now been available for over 40 years. Griseofulvin is active only against dermatophyte fungi and is inactive against all other fungi and bacteria. In order to exert its antifungal effect, it must be incorporated into keratinous tissue, where levels are much greater than serum levels, and therefore it has no effect if used topically.

The usual adult dose is 10–20 mg/kg/day for 6 weeks for treatment of larger lesions in tinea corporis.

Griseofulvin is well absorbed and absorption is enhanced if taken with a high-fat meal. In children, it may be given with milk. A 1000-mg dose produces a peak serum level of about 1–2 mg/L after 4 h, with a half-life of at least 9 h. An ultra-fine preparation of griseofulvin exists which is almost totally absorbed and permits the use of lower doses (typically 330–660 mg daily). This preparation is not available in the UK. Elimination is mainly through the liver and inactive metabolites are excreted in the urine. Less than 1% of a dose is excreted in urine in the active form, but some active drug is excreted in the faeces.

The duration of treatment with griseofulvin is dependent entirely on clinical response. Skin or hair infection usually requires 4–12 weeks’ therapy, but nail infections respond much more slowly; 6 months’ treatment is often required for fingernails, a year or more for toenail infections. Unfortunately, the rate of treatment failure or relapse in nail infection is high, and may reach up to 60%. Hence, terbinafine and itraconazole may be preferred agents.

Pityriasis versicolor

This is a common superficial skin infection caused by a yeast-like fungus, Malassezia furfur. The organism is a member of the normal skin flora and lives only on the skin because it has a growth requirement for medium-chain fatty acids present in sebum.

Clinical presentation

The condition usually appears as patches scattered over the trunk, neck and shoulders. These patches produce scales and may be pigmented in light-skinned individuals, appearing light brown in colour. In dark-skinned patients, the lesions may lose pigment and appear lighter than normal skin.

In some patients, Malassezia yeast is also associated with dandruff and seborrhoeic dermatitis, although the exact role of the yeast in causing this condition remains uncertain. In AIDS patients, seborrhoeic dermatitis may be quite extensive and sudden in onset.

Malassezia folliculitis can appear as greasy papules or pustules on the trunk or face of an HIV-infected individual.

Diagnosis

The diagnosis is made by microscopy of scrapings from the lesion. The specimen is examined for the presence of yeast cells and short hyphae. Culture is not usually required for diagnosis and, since it requires special culture media, is not routinely attempted.

Treatment

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