Treatment of fungal infections
Fungal infections are caused by organisms such as yeasts and molds, and can be classified into three main categories: noninvasive, systemic, and subcutaneous. Noninvasive infections, like athlete's foot and jock itch, often resolve with over-the-counter antifungals or hygienic measures. Prescription treatments include nystatin and azoles, with specific formulations targeting various conditions. Subcutaneous infections, less common in temperate areas, may require intravenous administration of amphotericin B, which, while effective, can be toxic. Systemic infections, such as histoplasmosis and coccidioidomycosis, are more complex and often necessitate long-term therapy, sometimes with high-potency medications like amphotericin B. Recent advancements in antifungal treatments include the approval of new drugs such as Rezafungin for invasive infections. Proper management is crucial, particularly for immunocompromised individuals, as untreated fungal infections can lead to severe complications or even death. Understanding the nature of the infection and choosing the right treatment is essential for effective recovery.
Treatment of fungal infections
Definition
Fungi are single-celled or multicelled organisms that include yeasts and molds. Fungal infections are classified three ways: as noninvasive, which are those infections that appear on skin, hair, or nails; as systemic, those infections that develop deep within the tissue and often circulate through the blood; and as subcutaneous, which occur below the skin but do not spread. The most appropriate approach to treating an antifungal infection balances efficacy and toxicity. Other considerations include the infected person’s health and the convenience and costs of treatment.
Infection Types
Noninvasive. Many superficial fungal infections, such as athlete’s foot (tinea pedis) and jock itch (tinea cruris), resolve spontaneously or with the use of a nonprescription or over-the-counter antifungal. Hygienic measures help in preventing initial spread and recurrence.
The first choice of a prescription drug to treat a superficial infection is nystatin (Nystop, Nyamyc, Nyata) or an azole. Nystatin has broad-spectrum activity and is available in cream, ointment, and powder formulations. Azoles are synthetic antifungals. Topical formulations of miconazole (Desenex, Lotrimin AF, Azolen, and Zeasorb), clotrimazole (FungiCURE and Lotrimin), econazole (Ecoza, Spectazole, and Ecostatin), sulconazole (Exelderm), and oxiconazole (Oxistat and Oxistat) are used for treating a wide spectrum of noninvasive fungal infections. The use of butoconazole (Gynazole-1, Mycelex-3), terconazole (Terazol 3 and Terazol 7), and ticonazole (Trosyd and Gyno-Trosyd) is limited to vaginal candidiasis.
Allylamines (amorolfine, butenafine, naftifine, and terbinafine) are broad-spectrum synthetic antifungals prescribed as topical agents, mainly to treat skin and nail infections. Amorolfine is available only as a lacquer for treating nail infections. The allylamines are not effective against infections caused by Candida species.
Nystatin vaginal suppositories and clotrimazole vaginal tablets are used to treat vaginal candidiasis. Cutaneous infections with surface manifestations, such as some forms of candidiasis, including paronychia (nail infection), can also be treated with topical antifungals. Other cutaneous infections, such as thrush, are managed with oral agents such as nystatin lozenges and griseofulvin tablets, capsules, or suspension.
The duration of treatment for fungal infections varies according to the type, location, and persistence of infection. For example, among noninvasive infections, vaginal candidiasis may require seven to ten days of treatment. In contrast, other infections may require several months of treatment before they resolve. Difficult cases of thrush, for example, that are treated with griseofulvin, may require six months of ongoing treatment. Neither superficial nor cutaneous infections elicit a lasting immune response, so recurring infection that requires retreatment is not uncommon.
Subcutaneous. Subcutaneous fungal infections, which affect skin and muscle tissue, are uncommon in temperate climates. Chromoblastomycosis and maduromycosis are caused by soil fungi that enter the body through open wounds. They produce local tumors, especially of the feet. Sporotrichosis occurs when thorns or sphagnum moss penetrate the skin and introduce pathogenic spores into the lymphatic system. Ulcers associated with lymph nodes then develop, often followed by systemic manifestations. All three infections can be treated with amphotericin B administered by intravenous infusion.
Amphotericin B is highly toxic and can lead to renal dysfunction. Cutaneous and lymphocutaneous sporotrichosis (nodular lymphangitis) can be treated with oral itraconazole or potassium iodide. Localized tumors associated with chromoblastomycosis and maduromycosis can be removed surgically.
Systemic. The main systemic fungal infections seen in the United States are histoplasmosis, coccidioidomycosis, blastomycosis, and cryptococcosis. All are difficult to manage and may require long-term, even lifelong, treatment. Some of these agents can become toxic at high doses or resistant after prolonged use.
Persons with symptomatic, mild-to-moderate, acute pulmonary histoplasmosis lasting more than four weeks should be treated with itraconazole for six to twelve weeks. Mild or moderate chronic or disseminated pulmonary histoplasmosis requires from six to twenty-four months of therapy with itraconazole in otherwise healthy persons and lifetime therapy in persons with acquired immunodeficiency syndrome (AIDS). Amphotericin B, administered for up to twelve weeks, is the drug of first choice for all cases of severe or systemic histoplasmosis. Once stabilized, an infected person can be switched to itraconazole on a schedule similar to that for less severe cases.
Coccidioidomycosis can be treated with itraconazole (200 milligrams [mg], twice daily) or fluconazole (400 to 600 mg per day) for three to six months. Fluconazole has fewer drug interactions than does itraconazole and is more easily absorbed, but it has a higher relapse rate. If the disease fails to improve or if it worsens, treatment should be switched to amphotericin B, starting at 1 to 1.5 mg per kilogram (mg/kg) of body weight per day. The dose of amphotericin B and its frequency should be reduced as improvement occurs. In coccidioidal meningitis, amphotericin can be infused directly into the cerebrospinal fluid. Even with aggressive therapy, regardless of the drug used, the risk of relapse is high. Therapy may need to be continued on a long-term basis.
Acute or chronic blastomycosis can be treated with itraconazole (400 mg per day) for six months, unless the condition is life-threatening. In this situation, therapy should start with amphotericin B (1.5 to 2.5 mg/kg per day), followed by itraconazole for up to six months once the infected person has stabilized.
Cryptococcosis is seen mainly in persons with compromised immunity. Aggressive therapy is always recommended, starting with amphotericin B at 0.7 mg/kg per day. Flucystatin 100 mg/kg may be added to this regimen. The two agents appear to work synergistically, allowing an early discontinuation of the amphotericin B. Flucytosine should not be used alone as Cryptococcus species quickly develop resistance to it. Intravenous Amphotericin B deoxycholate may also be recommended.
In 2023, the Food and Drug Administration approved the first new antifungal treatment used to treat invasive infections in over ten years—Rezafungin (REZZAYO). The once-weekly intravenous drug treats candidemia and invasive candidiasis. Other anti-fungal drugs approved in the twenty-first century include Ibrexafungerp (Brexafemme), which is used for vulvovaginal candidiasis, and Oteseconazole (Vivjoa), which is used for patients with recurrent vulvovaginal candidiasis.
Impact
Untreated or under-treated invasive and systemic fungal infections can lead to serious complications and even death. The management of invasive and systemic fungal infections, especially in immunocompromised persons, requires close clinical supervision with periodic monitoring of dosage and periodic adjustment of dosage, if necessary.
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