Medication Summary
Successful therapy for serious systemic Candida infections requires initiation of antifungal therapy as early as possible, as soon as adequate culture results are obtained.
Different classes of antifungals are now available to manage any type of candidal infection. Azoles, fluconazole in particular, [51] have become the mainstay of therapy over the past few years. These include topical and systemic agents. Posaconazole is the most recent addition to this group of antifungals. Polyenes include amphotericin B, liposomal amphotericin B formulations, and topical nystatin. Allylamines include terbinafine, which is formulated in a topical preparation and an oral tablet. The newest group of antifungals is echinocandins, including caspofungin, micafungin, and anidulafungin. These drugs have shown excellent clinical efficacy, a low incidence of adverse events, a good safety profile, and ease of use. [61, 62]
Azole Antifungals
Class Summary
These agents are synthetic compounds that include 2 groups, imidazoles and triazoles. Triazoles have 3 atoms of nitrogen in the azole ring. Imidazoles have only two. The primary mechanism of action is inhibition of lanosterol 14-alpha-demethylase, an enzyme required for the synthesis of ergosterol, the main component of fungal cell membranes. Imidazole agents include miconazole, ketoconazole, and clotrimazole.
In August 2013, the FDA announced that clinicians should no longer prescribe ketoconazole (Nizoral, Janssen Pharmaceuticals) tablets as a first-line therapy for any fungal infection, including Candida and dermatophyte infections, because of the risk for severe liver injury, adrenal insufficiency, and adverse drug interactions. [42, 43] The FDA also cautioned that ketoconazole tablets should not be prescribed for any patient with underlying liver disease. The labeling changes do not apply to topical formulations of ketoconazole in creams, shampoos, foams, and gels. Oral ketoconazole is now indicated only for endemic mycoses in patients who fail to respond to or cannot tolerate other treatments.
Ketoconazole tablets were also withdrawn from the market in the European Union in July 2013. [42, 43]
Triazole agents, which are now the most commonly used azoles, include fluconazole, itraconazole, econazole, terconazole, butoconazole, and tioconazole. Newer triazoles (ie, voriconazole, posaconazole, ravuconazole) are active against fluconazole-resistant strains of Candida. Voriconazole and posaconazole have shown high efficacy against candidiasis in recent clinical trials. [56, 63, 64]
Topical agents are frequently used as front-line agents to manage localized or superficial forms of candidiasis such as cutaneous candidiasis, oropharyngeal candidiasis (OPC), and vulvovaginal candidiasis (VVC). These preparations are available as a cream for topical use, as troches for OPC, and as a vaginal suppositories or tablets for vaginitis.
Fluconazole (Diflucan)
Triazole with less effect on human sterol metabolism. Does not decrease cortisol and testosterone levels, as occurs with ketoconazole. Has fewer adverse effects and better tissue distribution than older systemic imidazoles. Available PO/IV and has demonstrated efficacy in topical and invasive forms of candidiasis. Available in 50-, 100-, 150-, and 200-mg tabs.
Daily dose varies with indication.
Itraconazole (Sporanox)
Has fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P450-dependent synthesis of ergosterol, a vital component of fungal cell membranes. Effective against broad range of fungi, including Candida species, and is indicated for treatment of cutaneous, oral, esophageal, and disseminated candidiasis.
Available IV, 100-mg caps, and oral solution at 10 mg/mL.
Caps require gastric acidity for absorption and should be taken with food to increase absorption. Liquid formulation increases bioavailability and decreases need for acidity for proper absorption.
Use of solution has been recommended in mucosal and invasive candidiasis, while caps can be used in onychomycosis and dermatophyte infections.
Voriconazole (Vfend)
Available as tablet, suspension and parenteral preparations. Effective as fluconazole against esophageal candidiasis, and as effective as amphotericin B deoxycholate in treatment of candidemia and invasive candidiasis. In Europe, it has been approved for "treatment of fluconazole-resistant serious invasive Candida infections (including C krusei)." Additionally, associated with fewer breakthrough fungal infections when used as empiric therapy in febrile neutropenic patients. FDA approved for esophageal candidiasis and candidemia.
Posaconazole (Noxafil)
Novel triazole antifungal agent. Blocks ergosterol synthesis of cell membrane by inhibiting enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. Action results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Approved for treatment of OPC, including OPC refractory to itraconazole and/or fluconazole and for prophylaxis of infections due to Candida and Aspergillus in patients who are at high risk, such as those undergoing stem cell transplants with graft versus host disease or with prolonged neutropenia due to a hematologic malignancy or its treatment.
Glucan synthesis inhibitors (echinocandins)
Class Summary
These agents inhibit the formation of fungal cell wall. The antifungal class has expanded with the approvals of caspofungin, micafungin, anidulafungin, and rezafungin. Indications are evolving but have been approved for complicated forms of invasive candidiasis, candidemia, disease refractory to other systemic antifungals, and intolerance to amphotericin B. They are broad spectrum and fungicidal against most Candida species, except C parapsilosis and C guilliermondii.
Caspofungin (Cancidas)
FDA approved to treat candidemia, invasive candidiasis, and esophageal candidiasis. Initially approved to treat refractory invasive aspergillosis. Also approved as empiric therapy for presumed fungal infections in febrile neutropenic patients. First of a new class of antifungal drugs (glucan synthesis inhibitors). Inhibits synthesis of (1,3) β -D-glucan, an essential component of fungal cell wall. This component is not found in mammalian cell walls.
Micafungin (Mycamine)
A member of a new class of antifungal agents, echinocandins, that inhibit cell wall synthesis. Echinocandins inhibit the synthesis of (1,3)-β -D-glucan, an essential component of the fungal cell wall, not present in mammalian cells. Indications include prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation, treatment of esophageal candidiasis, candidemia, and invasive candidiasis.
Anidulafungin (Eraxis)
One of the newer antifungal agents belonging to the echinocandin class. Also inhibits synthesis of (1,3)-β -D-glucan, an essential component of fungal cell walls. Indicated for treatment of esophageal candidiasis, candidemia, and other forms of candidal infections (eg, intra-abdominal abscesses, peritonitis).
Rezafungin (Rezzayo)
Once weekly IV echinocandin. It is indicated for treatment of candidemia and invasive candidiasis in adults who have limited or no alternative treatment options. Shown to have antifungal activity against C albicans, C glabrata, C parapsilosis, and C tropicalis.
Polyenes
Class Summary
These are broad-spectrum fungicidal agents. Mechanism of action is by insertion into fungal cytoplasmic membrane, causing increases in permeability. Membrane channel activity is increased at lower doses, and pores are formed at higher concentrations.
Amphotericin B (Fungizone, Amphocin)
One of the oldest antifungals, in use for more than 40 y, and the criterion standard of antifungal therapy.
In recent years, lipid formulations have been developed. Total dose must be adjusted depending on type of candidal infection being treated. Most patients receive total dose of 0.5-1.5 g.
Amphotericin B, lipid formulations (Amphotec, Abelcet, AmBisome)
Novel lipid formulations of amphotericin B that deliver higher concentrations of drug with a theoretical increase in therapeutic potential and decreased nephrotoxicity.
Formulation types include amphotericin B lipid complex (ABLC, Abelcet), amphotericin B colloidal dispersion (ABCD, Amphotec), and liposomal amphotericin B (L-AMB, AmBisome).
ABLC and ABCD approved for treating adults and children intolerant of conventional amphotericin B or with fungal infections refractory to conventional amphotericin B. L-AMB is approved for aspergillosis, candidiasis, cryptococcosis, and neutropenic patients with persistent fever on broad-spectrum antibiotics.
Nystatin (Mycostatin)
Fungicidal and fungistatic antibiotic obtained from Streptomyces noursei. Effective against various yeasts and yeastlike fungi. Changes permeability of fungal cell membrane after binding to cell membrane sterols, causing cellular contents to leak. Membrane channel activity is increased at lower doses, and pores are formed at higher concentrations.
Antimetabolite
Class Summary
Flucytosine is an antimetabolite originally developed for the treatment of leukemia.
Flucytosine (Ancobon)
It is deaminated to 5-fluorouracil in the fungal cell by an enzyme not present in mammalian cells, and inhibits RNA and protein synthesis. Active against Candida and Cryptococcus species and generally used in combination with amphotericin B. It has been used in studies in invasive candidiasis. Avoid use as single agent because of ability to quickly develop resistance in vivo.
Topical azoles
Class Summary
These agents are used extensively to treat common mucocutaneous uncomplicated forms of candidiasis.
Clotrimazole (Mycelex, Femizole-7)
Broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing death of fungal cells.
Butoconazole (Femstat-3, Gynazole-1)
Broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing death of fungal cells.
Use 2% vaginal cream. Available OTC.
Miconazole vaginal (Monistat, Micatin)
Damages fungal cell wall membrane by inhibiting biosynthesis of ergosterol. Membrane permeability is increased, causing nutrients to leak out, resulting in fungal cell death. Lotion preferred in intertriginous areas. If cream is used, apply sparingly to avoid maceration effects.
Tioconazole (Vagistat-1)
Damages fungal cell wall membrane by inhibiting biosynthesis of ergosterol. Membrane permeability is increased, causing nutrients to leak out, resulting in fungal cell death.
Terconazole vaginal (Terazol-7, Terazol-3)
Damages fungal cell wall membrane by inhibiting biosynthesis of ergosterol. Membrane permeability is increased, causing nutrients to leak out, resulting in fungal cell death.
Allylamines
Class Summary
These agents cause a deficiency of ergosterol within the fungal cell wall, causing fungal cell death.
Terbinafine (Daskil, Lamisil)
For treatment of paronychia; allylamine antifungal, which inhibits squalene epoxidase and decreases ergosterol synthesis, causing fungal-cell death.
Use medication until symptoms significantly improve.
Duration of treatment should be >1 wk but not >4 wk. May not be as effective for candidal infections as azole antifungals.
Antifungals, Systemic
Ibrexafungerp (Brexafemme)
The first and only treatment for vaginal yeast infections, which is both oral and non-azole, approved for the treatment of VVC. It is a triterpenoid antifungal agent that inhibits glucan synthase, an enzyme involved in the formation of 1,3-beta-D-glucan, an essential component of the fungal cell wall.
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A moist, erosive, pruritic patch of perianal skin and perineum (with satellite pustule formation) is demonstrated in this woman with extensive candidiasis. Courtesy of Matthew C. Lambiase, DO.
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Discrete superficial pustules developed within hours of birth on the hand of an otherwise healthy newborn. A potassium hydroxide preparation revealed spores and pseudomycelium, and culture demonstrated the presence of Candida albicans. Courtesy of Matthew C. Lambiase, DO.
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Dry, red, superficially scaly, pruritic macules and patches on the penis represent candidal balanitis. Courtesy of Matthew C. Lambiase, DO.
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White plaques are present on the buccal mucosa and the undersurface of the tongue and represent thrush. When wiped off, the plaques leave red erosive areas. Courtesy of Matthew C. Lambiase, DO.
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Erythema, maceration, and satellite pustules in the axilla, accompanied by soreness and pruritus, result in a form of intertrigo. Courtesy of Matthew C. Lambiase, DO.
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A nailfold with candidal infection becomes erythematous, swollen, and tender with occasional discharge. Courtesy of Matthew C. Lambiase, DO.
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Soreness and cracks at the lateral angles of the mouth (angular cheilitis) are a frequent expression of candidiasis in elderly individuals. Courtesy of Matthew C. Lambiase, DO.
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Fine, superficial pustules on an erythematous patchy base are suggestive of candidiasis. Courtesy of Matthew C. Lambiase, DO.
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Candidal infection should be in the differential diagnosis when one or more nails become discolored, have subungual discoloration, have nailplate separation from the nailbed, and lack evidence of a dermatophyte. Courtesy of Matthew C. Lambiase, DO.
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Candida dermatitis in the diaper area. Courtesy of Hon Pak, MD.
