Fungal Infection Overview

Fungi can be found in many places including in soil, plants, on our skin, and in our bodies.

A ‘primary’ fungal infection (mycosis) occurs in immunocompetent patients, where ‘opportunistic’ infections are not usually pathogenic, and affect immunocompromised patients. The incidence of such infections is rising due to an increasing number of patients who are immunocompromised.

Many local fungal infections can be treated topically. If the infection isn’t able to be treated locally, does not resolve with local treatment, or if the patient is immunocompromised, then systemic treatment may be required.

Azole Antifungals

(Fluconazole, Itraconazole, Ketoconazole, Posaconazole and Voriconazole)

Azoles are fungistatic and break down fungal cell membranes by impairing synthesis of ergosterol, leading to fungal cell leakage; and then death from the lytic activity of the patient’s immune system. They can be used for a wide range of fungal infections and for most agents the dose, frequency and duration are dependent on the indication.

They can interact with a wide range of drugs, particularly those metabolised by cytochrome P450 enzymes. In particular azoles should not be administered to patients taking cisapride. Patients with hypersensitivity to an azole should only cautiously be prescribed a different azole due to the possibility of cross-reactivity.

Fluconazole and voriconazole can cause prolonged QT interval and increase the risk of arrhythmias, and itraconazole can precipitate or worsen heart failure, so these three azoles should be used with caution in patients with cardiovascular disease. Azole side effects are individual to each drug. Broadly speaking, the commonly occurring side effects with azole therapy are: rash, gastrointestinal (GI) upset, headache and elevated liver enzymes. Long term use of azoles can lead to worsening of peripheral neuropathy.

Monitoring of azoles depends on the agent used. In general the serum potassium concentration and liver function should be measured at baseline and repeated at regular intervals.

Echinocandins

(Caspofungin and Anidulafungin)

Echinocandins alter cell membrane permeability by inhibiting 1,3-beta-D-glucan synthase resulting in fungicidal activity against Candida spp. and fungistatic activity against Aspergillus spp.

Echinocandins are indicated for invasive candidiasis. Caspofungin is also used for oesophageal candidiasis, as empirical treatment of fungal infections in febrile neutropenic patients that don’t respond to antibacterials, and as second line treatment of invasive aspergillosis.

Patients who are hypersensitive to one echinocandin should not be prescribed the other due to a risk of cross sensitivity.

Side effects commonly include GI upset, rash, hypokalaemia and raised liver enzymes. They can also cause infusion reactions such as fever, hypotension, flushing, chills, rash, itch, dyspnoea and bronchospasm. To minimise infusion reactions echinocandins should be infused slowly.

Amphotericin

Amphotericin causes fungal cell death by irreversibly binding to the ergosterol in the fungal cell membranes, altering the permeability of the membranes, leading to intracellular leakage.

Amphotericin is indicated to treat severe systemic fungal infections, cryptococcal meningitis, oral/perioral candidiasis, as prophylaxis of liver transplant and HIV patients, and as empirical treatment for febrile neutropenic patients who are unresponsive to antibacterials. Preparations of amphotericin include amphotericin lipid complex (Abelcet®) and liposomal amphotericin (AmBisome®).

Amphotericin can lead to renal impairment, particularly if used with other nephrotoxic drugs such as aminoglycosides. Adverse effects can commonly include infusion reactions, although these tend to lessen with continued therapy. To reduce the risk of an infusion reaction occurring an antihistamine or paracetamol can be administered, or the rate of infusion can be slowed. Other common side effects include hyperglycaemia, anaemia, hypoxia, increased alkaline phosphatase, increased serum bilirubin, tachycardia, and hyponatraemia.

Monitoring should include renal function, electrolytes, hepatic function and complete blood picture.

Flucytosine (5-FC)

Flucytosine is converted to fluorouracil in fungal cells. The fluorouracil undergoes phosphorylation resulting in inhibition of fungal DNA synthesis and also affecting protein synthesis by incorporating itself into fungal RNA.

It is only indicated to be used in conjunction with amphotericin to treat cryptococcal infections. It should be used in combination with another antifungal because flucytosine has a narrow spectrum of activity and fungal resistance can develop quickly.

Flucytosine should be stored within a tight temperature range of 15-25°C because it can precipitate at low temperatures, and form fluorouracil above 25°C. Side effects commonly experienced include rash and GI upset. Thrombocytopenia, anaemia, leucopenia and elevated liver enzymes are dose related and are more common when the plasma concentration exceeds 100mg/L.

During treatment with flucytosine a baseline blood count, renal and hepatic function should be measured and then monitored regularly.

Griseofulvin

Griseofulvin acts by disrupting the microtubule function of the fungal cells.

Indicated when topical treatment has failed or is not appropriate in treating dermatophyte infections, it is contraindicated in lupus erythematosus (may exacerbate) and severe hepatic disease.

The dose and the duration of treatment depends on what part of the body is being treated. Tinea of the skin and hair should be treated for between four and six weeks but may be longer for areas with a thicker keratin layer. Infections of the nails should be treated for up to 12 months as the treatment should continue until the infected nail has grown out.

Side effects include headache, GI upset, photosensitivity, rash, blurred vision, confusion, dizziness, fatigue, and taste disturbance. Some people find that consuming alcohol during a course of griseofulvin can cause skin flushing and an increased heart rate, so alcohol consumption during therapy is not recommended.

Terbinafine

Terbinafine inhibits ergosterol synthesis via inhibition of squalene epoxidase which leads to the disruption of cell membranes and cell death. It is fungicidal to dermatophytes and fungistatic against Candida albicans.

It is indicated to treat onychomycosis and dermatophyte infections when topical treatment is ineffective or not appropriate. The duration of treatment is dependent on the condition being treated, usually between 2-12 weeks.

Do not use terbinafine in patients with active, chronic, and/or severe hepatic disease. Adverse effects commonly include headache, GI upset, itch and/or rash, urticaria, temporary elevation of liver enzymes, arthralgia and myalgia. Reversible taste disturbance may also sometimes occur. It may worsen psoriasis, and so should be used cautiously in these patients.

Pentamidine

Used to treat or prevent Pneumocystis jiroveci (carinii) pneumonia (PCP). Its mode of action isn’t fully known and may include inhibition of the synthesis of protein, DNA, and RNA. It may also inhibit oxidative phosphorylation and has effects on the metabolism of folate. Pentamidine can interact with a wide variety of drugs.

Adverse effects are common and can be severe, with people suffering from AIDS more likely to be affected. Side effects are often encountered in the first week of intravenous treatment, possibly a result of accumulation of pentamidine in the tissues.

Side effects may present or persist weeks after the treatment has finished. Such side effects can include GI upset, taste disturbance, Stevens-Johnson syndrome, toxic epidermal necrolysis, confusion, dizziness, raised liver enzymes, nephrotoxicity, arrhythmias, hyper or hypo-glycaemia, pancreatitis, hypotension, electrolyte abnormalities, bronchospasm, thrombocytopenia or anaemia.

Side effects are less common with inhaled pentamidine, although it causes bronchospasm and cough, and should be used with caution in smokers or those suffering from asthma. A bronchodilator can be used prior to using the inhaled pentamidine to reduce this adverse effect. Inhaled pentamidine should not be used in patients suffering from active tuberculosis, because this increases the risk of transmission to others.

An ECG should be taken at baseline and regularly during treatment. Blood pressure, kidney and liver function, blood glucose, complete blood count, serum potassium, and serum calcium should all be monitored regularly during therapy.

Summary

Fungal infections requiring systemic treatment are often those that are hard to treat, fail topical therapy, or occur in immunocompromised patients. There are a broad range of systemic fungal conditions with an equally broad range of treatment options. Selection of an appropriate agent needs to account for the infection being treated, what agents have been used in the past, and other medications the patient is taking. Clinicians need to also ensure that an appropriate treatment duration is observed to ensure adequate resolution of the infection.

References:

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