The treatments used to manage Candida infections vary substantially and are based on the anatomic location of the infection, the patients' underlying disease and immune status, the patients' risk factors for infection, the specific species of Candida responsible for infection, and, in some cases, the susceptibility of the Candida species to specific antifungal drugs.
There have been significant changes in the management of candidiasis in the last few years, particularly related to the appropriate use of echinocandins and expanded-spectrum azoles for candidemia, other forms of invasive candidiasis, and mucosal candidiasis.
Current guidelines were published in 2016 by the Infectious Disease Society of America (IDSA), [39] These recommendations include the echinocandins caspofungin, micafungin, and anidulafungin, along with fluconazole, as well as lipid formulations of amphotericin B in various situations.
Echinocandins are the recommended drugs of choice for candidemia and invasive candiasis. Fluconazole is still an alternative if echinocandisns are not readily available.
A revision of data outcomes on treatment of invasive candidiasis in clinical trials appears to favor use of echinocandins in terms of increased rate of survival. This type of finding may have an impact on future treatment recommendations and strategies of drug use for invasive candidiasis in different groups of patients. [40, 41] Safety compared to other alternatives is another important consideration favoring use of achinocandins in this cases. [36]
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Ketoconazole tablets were also withdrawn from the market in the European Union in July 2013.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]
The therapeutic options available for the management of invasive candidiasis and candidemia have continued to increase with the addition of newer echinocandins [44, 45] and triazoles.
Newer investigational agents already in clinical trials include ibrexafungerp, a glucan-synthase inhibitor, that was approved in 2021 for the treatment of vulvo-vagin*l candidiasis in oral formulation. The parenteral formulation is still under investigation for the treatment of candidemia and invasive candidiasis. [46] Rezafungin is a long-acting echinocandin given wekly is being studied for candidemia and invasive candidiasis. [47]
Cutaneous candidiasis
Most localized cutaneous candidiasis infections may be treated with any number of topical antifungal agents (eg, clotrimazole, econazole, ciclopirox, miconazole, ketoconazole, nystatin). If the infection is a paronychia, the most important aspect of therapy is drainage of the abscess, followed by oral antifungal therapy with either fluconazole or itraconazole. In cases of extensive cutaneous infections, infections in immunocompromised patients, folliculitis, or onychomycosis, systemic antifungal therapy is recommended. For Candida onychomycosis, oral itraconazole (Sporanox) appears to be most efficacious. Two treatment regimens are available: the daily dose of itraconazole taken for 3-6 months or the pulsed-dose regimen that requires a slightly higher daily dose for 7 days, followed by 3 weeks of no drug administration. The cycle is repeated every month for 3-6 months.
Gastrointestinal candidiasis
Oropharyngeal candidiasis
Oropharyngeal candidiasis OPC can be treated with either topical antifungal agents (eg, nystatin, clotrimazole, amphotericin B oral suspension) or systemic oral azoles (fluconazole, itraconazole, or posaconazole).
Infections in HIV-positive patients tend to respond more slowly and, in approximately 60% of patients, recur within 6 months of the initial episode. Approximately 3-5% of patients with advanced HIV infection (CD4 cell counts < 50/µL) may develop refractory OPC. In these situations, in addition to attempting correction of the immune dysfunction with HAART, higher doses of fluconazole (up to 800 mg/d) or itraconazole (up to 600 mg/d) can be attempted. Posaconazole suspension at 400 mg orally twice per day has also yielded excellent results in such patients. Additionally, caspofungin 50 mg/d IV and anidulafungin 100 mg/d IV have also yielded excellent efficacy in such patents. Amphotericin B is rarely necessary to treat such cases, but, when used, low doses of amphotericin B can be used (0.3-0.7 mg/kg) and have been shown to be effective.
Candidaesophagitis
Candida esophagitis requires systemic therapy with fluconazole for 14-21 days. Parenteral therapy with fluconazole may be required initially if the patient is unable to take oral medications. Daily suppressive antifungal therapy with fluconazole 100-200 mg/d is effective for preventing recurrent episodes, but it should be used only if the recurrences become frequent or are associated with malnutrition due to poor oral intake and wasting syndrome. Recommended alternatives for fluconazole-refractory disease include itraconazole, voriconazole, caspofungin, micafungin, anidulafungin, and amphotericin B.
Genitourinary tract candidiasis
Vulvovagin*l candidiasis (VVC) can be managed with either topical antifungal agents or a single dose of oral fluconazole. [2] A single dose of oral fluconazole (150 mg) in acute episodes of VVC has been shown to yield clinical and microbiological efficacy as good as or better than topical antifungal agents. A small percentage (< 5%) of women experience chronic recurrent VVC infections, which often require long-term or prophylactic oral azole therapy for control. In such patients, the recommended regimen includes fluconazole 150 mg every other day for 3 doses, followed by weekly fluconazole 150-200 mg for 6 months. [1] This regimen prevents further recurrence in more than 80% of women. In pregnant women, just one or two oral doses of fluconazole for vagin*l candidiasis during pregnancy was not associated with significantly increased risks of stillbirth or neonatal death, according to a 2018 Scandinavian cohort study. [48]
Ibrexafungerp (Brexafemme), the first and only treatment for vagin*l yeast infections which is both oral and a non-azole, has been approved for the treatment of VVC. It mechanism of action is glucan synthase inhibition withbroad-spectrum anti-Candida fungicidal activity. Approval was based on positive results from two Phase 3, randomized, double-blind, placebo-controlled, multicenter studies (VANISH-303 and VANISH-306), in which oral ibrexafungerp demonstrated efficacy and a favorable tolerability profile in women with VVC. [49, 50]
For asymptomatic candiduria, therapy generally depends on the presence or absence of an indwelling Foley catheter. Candiduria frequently resolves by simply changing the Foley catheter (20-25% of patients). Thus, most experts agree that asymptomatic candiduria associated with a Foley catheter does not require treatment in most cases. However, eradicating candiduria prior to any form of instrumentation or urological manipulation is prudent.
Candida cystitis in noncatheterized patients should be treated with fluconazole at 200 mg/d orally for at least 10-14 days.
For Candida cystitis in catheterized patients, the first step is always to remove the nidus of infection. Thus, the Foley catheter should be removed or replaced prior to initiating antifungal therapy. If the candiduria persists after the catheter change, then patients can be treated with 200 mg/d of fluconazole orally for 14 days. Alternative therapy includes amphotericin B bladder irrigation. However, its use for the treatment of funguria is significantly limited, primarily because of the required maintenance of a urinary catheter; lack of adequate studies to define the dose, duration, and method of administration; restriction of its use to uncomplicated lower urinary tract infections; and the availability of more convenient treatment options (eg, oral fluconazole therapy). The use of amphotericin B bladder irrigation is rarely needed. Administering intravenous amphotericin B to treat candiduria is rarely necessary.
Renal candidiasis
Regardless of whether the infection involves hematogenous dissemination to the kidney or ascending infection (pyelonephritis), systemic antifungal therapy is required. The most recent comparative studies indicate that fluconazole at 400 mg/d intravenously or orally for a minimum of 2 weeks is as effective as amphotericin B without the toxicities normally associated with amphotericin B. For amphotericin B, the daily dose is 0.5-0.7 mg/kg intravenously for a total dose of 1-2 g administered over a 4- to 6-week period.
Candidemia
This requires treatment in all patient populations. Current recommendations depend on the presence or absence of neutropenia. (ref 28)
In patients without neutropenia, an echinocandin is recommended as initial therapy and fluconazole an acceptable alternative in certain circ*mstamces in most cases of candidemia and disseminated candidiasis. Transition to fluconazole is also possible when clinically stable and a fluconazole-susceptible strain is identified. Studies conducted by the MSG have demonstrated that fluconazole at a dose of 400 mg/d is as efficacious as amphotericin B. In addition, fluconazole has several advantages, including lower nephrotoxicity rates (< 2%) and ease of use because of the high degree of bioavailability and the long half-life of the drug. [51] Thus, once the gastrointestinal tract is functional, the parenteral antifungal may be switched to the oral formulation with the same efficacy. Alternative options listed below need to be considered depending on history of previous exposure to antifungals, the probability of fluconazole resistance according to the species of Candida recovered, the presence of comorbid conditions, and the clinical status of the patient. [52]
An echinocandin is recommended for candidemia in most patients with neutropenia. Lipid amphotericin B is an alternative that can be considered. Fluconazole is an alternative in patients who are less critically ill and who have no recent azole exposure. Voriconazole can be used when additional mold coverage is desired.
The standard recommended dose for fluconazole is 800 mg as the loading dose, followed by fluconazole at a dose of 400 mg/d for at least 2 weeks of therapy after a demonstrated negative blood culture result or clinical signs of improvement. This treatment regimen can be used for infections due to C albicans, C tropicalis, C parapsilosis, C kefyr, C dubliniensis, C lusitaniae, and C guilliermondi.
A critical component in the management of candidemia and disseminated candidiasis is the removal of the focus of infection, such as intravenous and Foley catheters.
Available echinocandins for candidemia include the following:
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Caspofungin (Cancidas) can be initiated as a 70-mg loading dose, followed by 50 mg/d intravenously to complete a minimum of 2 weeks of antifungals after improvement and after blood cultures have cleared. Caspofungin is a broad-spectrum semisynthetic echinocandin. It is an effective alternative for severe mucosal infections and systemic infections due to Candida, especially those due to non- albicans Candida species such as C glabrata.
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Anidulafungin can be initiated as a 200-mg loading dose, followed by 100 mg intravenously to complete a minimum of 2 weeks of antifungals after improvement and after blood cultures have cleared. Anidulafungin is a broad-spectrum echinocandin. It is an effective alternative for severe mucosal infections and systemic infections due to Candida, especially those due to non- albicans Candida species such as C glabrata. [53]
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Micafungin can be administered at 100 mg/d intravenously to complete a minimum of 2 weeks of antifungals after improvement and after blood cultures have cleared. Micafungin is a broad-spectrum echinocandin. It has been shown to be an effective alternative for severe mucosal infections and systemic infections due to Candida, especially those due to non- albicans Candida species such as C glabrata. [54]
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Rezafungin (Rezzayo) is initiated with a 400-mg IV loading dose, then 200 mg intravenously once weekly for up to 4 doses. It is indicated for adults who have limited or no alternative treatment options for candidemia and invasive candidiasis. Shown to have antifungal activity against C albicans, C glabrata, C parapsilosis, and C tropicalis. [55]
Additional options for candidemia include the following:
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Voriconazole can be initiated at 6 mg/kg intravenously or orally twice per day, followed by 3 mg/kg orally twice per day or 200 mg orally twice per day. Based on the findings from a global multicenter clinical trial, voriconazole has also been approved for use in candidemia in patients who are not neutropenic. [56]
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Amphotericin B deoxycholate can be administered at 0.7 mg/kg/d intravenously for a total dose of 1-2 g over a 4- to 6-week period.
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Liposomal preparations of amphotericin B have comparable efficacy to conventional amphotericin B, but renal toxicity is considerably less common with the former.
Chronic mucocutaneous candidiasis
This condition is generally treated with oral azoles, such as fluconazole at a dose of 100-400 mg/d or itraconazole at a dose of 200-600 mg/d until the patient improves. The initial therapy for acute infection is always followed by maintenance therapy with the same azole for life.
Hepatosplenic candidiasis
Induction therapy is initially started with amphotericin B deoxycholate for at least 2 weeks, followed by consolidation therapy with fluconazole at a dose of 400 mg/d for an additional 4-12 weeks depending on the response.
Respiratory tract candidiasis
If the diagnosis is established based on biopsy findings, then the infection is treated as disseminated candidiasis.
Invasive candidiasis
Empirical treatment options for suspected invasive candidiasis include the following:
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Empirical antifungal therapy should be considered for critically ill patients with risk factors for invasive candidiasis and no other cause of fever, and it should be based on clinical assessment of risk factors, serologic markers for invasive candidiasis, and/or culture data from nonsterile sites. (Its benefits have not been clearly determined.) [57]
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This continues to be a problematic decision since criteria for starting empirical antifungal therapy remain poorly defined. Empirical therapy in persistently febrile and neutropenic patients should cover infections caused by yeasts and molds.
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The choice of drugs in nonneutropenic patients is similar to that for proven candidiasis. Recommended agents include fluconazole or an echinocandin.
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In neutropenic patients, a lipid formulation of amphotericin B, caspofungin, or voriconazole is recommended. Azoles should not be used for empirical therapy in individuals who have received an azole for prophylaxis.
Disseminated candidiasis with end organ infection
Disseminated candidiasis with end organ involvement requires an individualized approach. Thus, the manifestation of invasive candidiasis involving localized structures, such as in Candida osteomyelitis, arthritis, endocarditis, pericarditis, and meningitis, requires prolonged antifungal therapy for at least 4-6 weeks. The optimum dosage and duration of therapy for various types of deep candidal infection have not been definitively determined.
The standard recommended dose for most Candida infections is fluconazole at 800 mg as the loading dose, followed by fluconazole at a dose of 400 mg/d either intravenously or orally for at least 2 weeks of therapy after a demonstrated negative blood culture result or clinical signs of improvement.
The echinocandins have become first-line therapy for this type of infection in many situations because of their efficacy and low incidence of adverse events and drug interactions.
Caspofungin (Cancidas) [58] can be initiated as a 70-mg loading dose, followed by 50 mg/d intravenously to complete a minimum of 2 weeks of antifungals after improvement and after blood cultures have cleared. Caspofungin is a broad-spectrum semisynthetic echinocandin. It is an effective alternative for severe mucosal infections and systemic infections due to Candida, especially those due to non-albicans Candida species such as C glabrata.
Anidulafungin can be initiated as a 200-mg loading dose, followed by 100 mg intravenously to complete a minimum of 2 weeks of antifungals after improvement and after blood cultures have cleared. Anidulafungin is a broad-spectrum echinocandin. It is an effective alternative for severe mucosal infections and systemic infections due to Candida, especially those due to non-albicans Candida species such as C glabrata. [53]
Micafungin can be administered at 100 mg/d intravenously to complete a minimum of 2 weeks of antifungals after improvement and after blood cultures have cleared. Micafungin is a broad-spectrum echinocandin. It has been shown to be an effective alternative for severe mucosal infections and systemic infections due to Candida, especially those due to non-albicans Candida species such as C glabrata. [54]
Voriconazole can be initiated at 6 mg/kg intravenously or orally twice per day, followed by 3 mg/kg orally twice per day or 200 mg orally twice per day. Based on the findings from a global multicenter clinical trial, voriconazole has also been approved for use in candidemia in patients who are not neutropenic. [56]
Rezafungin (Rezzayo) is initiated with a 400-mg IV loading dose, then 200 mg IV once weekly for up to 4 doses. It is indicated for adults who have limited or no alternative treatment options for candidemia and invasive candidiasis. Shown to have antifungal activity against C albicans, C glabrata, C parapsilosis, and C tropicalis. [55]
Amphotericin B deoxycholate has been an alternative to fluconazole for many years. However, with the advent of the newer azoles and the echinocandins, its role as a primary or secondary option needs to be reconsidered. The dose for amphotericin B deoxycholate is 0.5-0.7 mg/kg/d intravenously to achieve a minimum of 1- to 2-g total dose. For the treatment of invasive candidiasis caused by less-susceptible species, such as C glabrata and C krusei, higher doses (up to 1 mg/kg/d) should be considered.
Liposomal preparations of amphotericin B are recommended at doses between 3 and 5 mg/kg/d when used for invasive candidiasis.
Special situations involving antifungal resistance
Several of the Candida species require special mention because of their known intrinsic resistance to antifungals.
Because C glabrata is known to be resistant to fluconazole in 15-25% of cases and has decreased susceptibility to most antifungals, C glabrata infections require a change in conventional antifungal therapy. The drugs of choice for such infections are the echinocandins: caspofungin 70 mg intravenously as a loading dose, followed by 50 mg/d; anidulafungin 200-mg loading dose, followed by 100 mg/d; or micafungin 100 mg/day intravenously. An alternative is voriconazole at 6 mg/kg administered twice on the first day, followed by 3 mg/kg twice per day or 200 mg twice per day orally; other options include amphotericin B deoxycholate (1 mg/kg/d), or lipid preparations of amphotericin B at 3-5 mg/kg/d.
If in vitro susceptibility assays are available, it may be worthwhile to establish the in vitro susceptibility of the C glabrata strain to fluconazole. If the MIC is less than 8 μg/mL, then fluconazole can be used at 400 mg/d intravenously or orally.
C krusei infections necessitate the use of an agent other than fluconazole, because this organism is intrinsically resistant to fluconazole and has a decreased susceptibility to itraconazole, ketoconazole, and amphotericin B. Thus, the preferred regimen includes echinocandins (caspofungin, anidulafungin, or micafungin) voriconazole, or amphotericin B at 1 mg/kg/d. Infections due to C lusitaniae or C guilliermondi necessitate the use of fluconazole, voriconazole, or the echinocandins because these isolates are frequently intrinsically resistant to amphotericin B or develop resistance to amphotericin B while the patient is on therapy.
Alternative antifungal regimens
Alternative regimens may be considered in patients who are intolerant to the treatment regimens or when the infection is refractory to the antifungal regimen. The combination of amphotericin B and flucytosine has been recommended in several special situations. For instance, this combination has been used in immunocompromised patients with endophthalmitis, meningitis, or osteomyelitis. Flucytosine appears to interact synergistically with amphotericin B in animal models.
The role of other combinations of antifungals to treat complicated Candida infections needs to be evaluated. A human recombinant monoclonal antibody against heat shock protein 90 was recently reported to significantly improve outcomes in patients treated with lipid-associated amphotericin B for confirmed invasive candidiasis. [59] However, larger randomized trials need to be performed before this drug can be used clinically.
