Fungal infections
Candidal vulvitis can be treated locally with cream but is almost invariably associated with vaginal infection which should also be treated. Vaginal candidiasis is treated primarily with antifungal pessaries or cream inserted high into the vagina (including during menstruation). Single-dose preparations offer an advantage when compliance is a problem. Local irritation may occur on application of vaginal antifungal products.
Imidazole drugs (clotrimazole, econazole, and miconazole) are effective against candida in short courses of 3 to 14 days according to the preparation used. Vaginal applications may be supplemented with antifungal cream for vulvitis and to treat other superficial sites of infection.
Nystatin cream is used in cases of vulvitis and infection of other superficial sites. Nystatin stains clothing yellow.
Oral treatment of vaginal infection with fluconazole or itraconazole is also effective; oral ketoconazole has been associated with fatal hepatotoxicity
Immunocompromised patients
Immunocompromised patients are at particular risk of fungal infections and may receive antifungal drugs prophylactically; oral imidazole or triazole antifungals are the drugs of choice for prophylaxis. Fluconazole is more reliably absorbed than itraconazole and ketoconazole and is considered less toxic than ketoconazole for long-term use.
Amphotericin by intravenous infusion is used for the empirical treatment of serious fungal infections. Fluconazole is used for treating Candida albicans infection. Caspofungin is licensed for the empirical treatment of systemic fungal infections (such as those involving Candida spp. or Aspergillus spp.) in patients with neutropenia.
Recurrent vulvovaginal candidiasis
Recurrence of vulvovaginal candidiasis is particularly likely if there are predisposing factors such as antibacterial therapy, pregnancy, diabetes mellitus and possibly oral contraceptive use. Reservoirs of infection may also lead to recontamination and should be treated; these include other skin sites such as the digits, nail beds, and umbilicus as well as the gastro-intestinal tract and the bladder. The partner may also be the source of re-infection and, if symptomatic, should be treated with cream at the same time.
Treatment against candida may need to be extended for 6 months in recurrent vulvovaginal candidiasis. Some recommended regimens [all unlicensed] include:
· fluconazole by mouth 100 mg (as a single dose) every week for 6 months
· clotrimazole vaginally 500-mg pessary (as a single dose) every week for 6 months
· itraconazole by mouth 400 mg (as 2 divided doses on one day) every month for 6 months.
Imidazole antifungals
The imidazole antifungals include clotrimazole, econazole, ketoconazole, sulconazole, and tioconazole. They are used for the local treatment of vaginal candidiasis and for dermatophyte infections.
KETOCONAZOLE
Indications
skin, hair, and mucosal mycoses that cannot be treated with other antifungals (including dermatophytoses, pityrosporum folliculitis, cutaneous candidiasis, chronic mucocutaneous candidiasis, oropharyngeal and oesophageal candidiasis, chronic recurrent vaginal candidiasis); systemic mycoses that cannot be treated with other antifungals (including histoplasmosis, blastomycosis, coccidioidomycosis, paracoccidiodomycosis)
Cautions
the CSM has advised that prescribers should weigh the potential benefits of ketoconazole treatment against the risk of liver damage and should carefully monitor patients both clinically and biochemically. It should not be used by mouth for superficial fungal infections.
predisposition to adrenocortical insufficiency; avoid in porphyria ; pregnancy .
Hepatotoxicity
Potentially life-threatening hepatotoxicity reported very rarely; risk of hepatotoxicity greater if given for longer than 14 days. Monitor liver function before treatment, then on weeks 2 and 4 of treatment, then every month. Avoid or use with caution if abnormal liver function tests (avoid in active liver disease) or if history of hepatotoxicity with other drugs.
Counselling
Patients should be told how to recognise signs of liver disorder and advised to seek prompt medical attention if symptoms such as anorexia, nausea, vomiting, fatigue, abdominal pain, jaundice, or dark urine develop
Contra-indications
hepatic impairment; breast-feeding
Side-effects
nausea, vomiting, abdominal pain; pruritus; less commonly diarrhea, headache, dizziness, drowsiness, and rash; very rarely fatal liver damage, dyspepsia, raised intracranial pressure, adrenocortical insufficiency, erectile dysfunction, menstrual disorders, azoospermia (with high doses), gynaecomastia, thrombocytopenia, photophobia, and alopecia
Dose
200 mg once daily, increased if response inadequate to 400 mg once daily; continued until symptoms have cleared and cultures negative (usually for 4 weeks in dermatophytoses, 2–3 weeks for oral and cutaneous candidiasis, 1–2 months for hair infections); child body-weight 15–30 kg, 100 mg once daily; body-weight over
Chronic, recurrent vaginal candidiasis, 400 mg once daily for 5 days
ITRACONAZOLE
Cautions
absorption reduced in AIDS and neutropenia (monitor plasma-itraconazole concentration and increase dose if necessary); susceptibility to congestive heart failure (see also CSM advice, below); renal impairment; pregnancy and breast-feeding; interactions: (antifungals, triazole)
Hepatotoxicity
Potentially life-threatening hepatotoxicity reported very rarely. Monitor liver function—discontinue if signs of hepatitis develop; avoid or use with caution if history of hepatotoxicity with other drugs or in active liver disease; use with caution in patients receiving other hepatotoxic drugs
Counselling
Patients should be told how to recognise signs of liver disorder and advised to seek prompt medical attention if symptoms such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine develop
CSM advice (heart failure)
Following rare reports of heart failure, the CSM has advised caution when prescribing itraconazole to patients at high risk of heart failure. Those at risk include:
· patients receiving high doses and longer treatment courses;
· older patients and those with cardiac disease;
· patients receiving treatment with negative inotropic drugs, e.g. calcium channel blockers.
Side-effects
very rarely nausea, vomiting, dyspepsia, abdominal pain, diarrhoea, constipation, jaundice, hepatitis (see also Hepatotoxicity above), heart failure (see CSM advice above), pulmonary oedema, headache, dizziness, peripheral neuropathy (discontinue treatment), menstrual disorder, hypokalaemia, rash, pruritus, Stevens-Johnson syndrome, and alopecia; with intravenous injection, very rarely hypertension and hyperglycaemia
Indications & Dose
By mouth, oropharyngeal candidiasis, 100 mg daily (200 mg daily in AIDS or neutropenia) for 15 days; see also under Sporanox® oral liquid below
Vulvovaginal candidiasis, 200 mg twice daily for 1 day
Pityriasis versicolor, 200 mg daily for 7 days
Tinea corporis and tinea cruris, either 100 mg daily for 15 days or 200 mg daily for 7 days
Tinea pedis and tinea manuum, either 100 mg daily for 30 days or 200 mg twice daily for 7 days
Onychomycosis, either 200 mg daily for 3 months or course (‘pulse') of 200 mg twice daily for 7 days, subsequent courses repeated after 21-day interval; fingernails 2 courses, toenails 3 courses
Histoplasmosis, 200 mg 1–2 times daily
Systemic aspergillosis, candidiasis and cryptococcosis including cryptococcal meningitis where other antifungal drugs inappropriate or ineffective, 200 mg once daily (candidiasis 100–200 mg once daily) increased in invasive or disseminated disease and in cryptococcal meningitis to 200 mg twice daily
Maintenance in AIDS patients to prevent relapse of underlying fungal infection and prophylaxis in neutropenia when standard therapy inappropriate, 200 mg once daily, increased to 200 mg twice daily if low plasma-itraconazole concentration (see Cautions)
Prophylaxis in patients with haematological malignancy or undergoing bone-marrow transplant, see under Sporanox® oral liquid below
By intravenous infusion, systemic aspergillosis, candidiasis and cryptococcosis including cryptococcal meningitis where other antifungal drugs inappropriate or ineffective, histoplasmosis, 200 mg every 12 hours for 2 days, then 200 mg once daily for max. 12 days
child and elderly safety and efficacy not established
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martindale
Genital candidiasis responds well to topical antifungal treatment with creams or pessaries. Uncomplicated vaginitis responds to short-course topical therapy with azoles such as butoconazole, clotrimazole, miconazole, terconazole, or tioconazole, to topical nystatin, or to oral therapy with fluconazole, itraconazole, or ketoconazole. Complicated disease, which occurs in up to 10% of cases, requires at least 7 days of treatment with topical antifungals or an oral dose of fluconazole repeated 72 hours later.Vulvovaginal candidiasis with non-albicans species may not respond to topical azoles, in which case topical boric acid or topical flucytosine are often effective. In pregnancy, topical azoles are recommended and appear to be more effective than nystatin; treatment is given for 7 days. Recurrent vaginal candidiasis should be treated for at least 6 months with daily oral ketoconazole, daily or monthly oral itraconazole, weekly oral fluconazole, or weekly topical clotrimazole. Yogurt preparations containing Lactobacillus spp. have been used in the treatment and prevention of vaginal candidiasis in an attempt to restore the natural vaginal flora but evidence to support their use is limited.
Candidiasis
Candida spp. are commensal fungi commonly found in the gastrointestinal tract, mouth, and vagina; they may become pathogenic when natural defence mechanisms are impaired. C. albicans is the species most commonly associated with infection although infections with other Candida spp., notably C. glabrata (Torulopsis glabrata), C. krusei, C. lusitaniae, C. parapsilosis, and C. tropicalis, also occur and together are commonly referred to as non-albicans species. Predisposing factors for candidiasis include antibacterial therapy, skin or mucosal breach, abdominal surgery, debility, diabetes mellitus, pregnancy, and neutropenia and T-cell immunodeficiency; candidiasis often occurs in patients with HIV infection.
Candidiasis (or candidosis) may be classified as mucocutaneous or superficial, invasive (deep-organ), or disseminated. Mucocutaneous candidiasis includes infections of the oropharynx, genital organs, and skin. Oropharyngeal and vulvovaginal candidiasis are commonly termed thrush. Most superficial infections may be effectively treated with topical antifungals, although the rare chronic mucocutaneous candidiasis syndrome usually requires systemic treatment. The choice of antifungal should be guided by the availability of an appropriate formulation for the site of infection, toxicity, and the duration of treatment.
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FLUCONAZOLE
Cautions
renal impairment; pregnancy and breast-feeding; concomitant use with hepatotoxic drugs, monitor liver function with high doses or extended courses—discontinue if signs or symptoms of hepatic disease (risk of hepatic necrosis); susceptibility to QT interval prolongation; interactions: Appendix 1 (antifungals, triazole)
Side-effects
nausea, abdominal discomfort, diarrhoea, flatulence, headache, rash (discontinue treatment or monitor closely if infection invasive or systemic); less frequently dyspepsia, vomiting, taste disturbance, hepatic disorders, hypersensitivity reactions, anaphylaxis, dizziness, seizures, alopecia, pruritus, toxic epidermal necrolysis, Stevens-Johnson syndrome (severe cutaneous reactions more likely in AIDS patients), hyperlipidaemia, leucopenia, thrombocytopenia, and hypokalaemia reported
Dose
vaginal candidiasis (see also Recurrent Vulvovaginal Candidiasis) and candidal balanitis, by mouth, a single dose of 150 mg
Mucosal candidiasis (except genital), by mouth, 50 mg daily (100 mg daily in unusually difficult infections) given for 7–14 days in oropharyngeal candidiasis (max. 14 days except in severely immunocompromised patients); for 14 days in atrophic oral candidiasis associated with dentures; for 14–30 days in other mucosal infections (e.g. oesophagitis, candiduria, non-invasive bronchopulmonary infections); child by mouth or by intravenous infusion, 3–6 mg/kg on first day then 3 mg/kg daily (every 72 hours in neonate up to 2 weeks old, every 48 hours in neonate 2–4 weeks old)
Tinea pedis, corporis, cruris, pityriasis versicolor, and dermal candidiasis, by mouth, 50 mg daily for 2–4 weeks (for up to 6 weeks in tinea pedis); max. duration of treatment 6 weeks
Invasive candidal infections (including candidaemia and disseminated candidiasis) and cryptococcal infections (including meningitis), by mouth or intravenous infusion, 400 mg on first day then 200–400 mg daily; max. 800 mg daily in severe infections [unlicensed dose]; treatment continued according to response (at least 8 weeks for cryptococcal meningitis); child 6–12 mg/kg daily (every 72 hours in neonate up to 2 weeks old, every 48 hours in neonate 2–4 weeks old); max. 400 mg daily
Prevention of relapse of cryptococcal meningitis in AIDS patients after completion of primary therapy, by mouth, 200 mg daily or by intravenous infusion, 100–200 mg daily
Prevention of fungal infections in immunocompromised patients, by mouth or by intravenous infusion, 50–400 mg daily adjusted according to risk; 400 mg daily if high risk of systemic infections e.g. following bone-marrow transplantation; commence treatment before anticipated onset of neutropenia and continue for 7 days after neutrophil count in desirable range; child according to extent and duration of neutropenia, 3–12 mg/kg daily (every 72 hours in neonate up to 2 weeks old, every 48 hours in neonate 2–4 weeks old); max. 400 mg daily
Resistance
The emergence of strains of Candida spp. resistant to fluconazole has become increasingly important, particularly in immunocompromised patients receiving long-term prophylaxis with fluconazole. In addition to resistance in C. albicans, infections with C. dubliniensis, C. glabrata, and C. krusei, all of which may be less sensitive to fluconazole than C. albicans, have been noted in these patients, and secondary resistance of C. glabrata has been reported during fluconazole therapy. Resistance to fluconazole has been reported to occur more frequently than resistance to either ketoconazole or itraconazole and may be related to the widespread use of this drug. Cross-resistance with other azoles and with amphotericin B has been reported.
Fluconazole resistance has also been reported in Cryptococcus neoformans and Histoplasma capsulatum. Histoplasmosis developed during treatment with fluconazole in a patient with HIV infection. Fluconazole-resistant C. neoformans has been isolated from an immunocompetent patient who had not been exposed to azole antifungals previously.
