Fungal infections

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42 Fungal infections

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.

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

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.

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

Candida balanitis

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

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.

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.