Candidiasis Treatment Guidelines

Oropharyngeal (thrush)

MILD
Clotrimazole troches 10 mg (U.S. only) five times per day for 7 to 14 days OR
Miconazole mucoadhesive buccal 50 mg tablet (U.S. only; Oravig) apply to the mucosal surface over the canine fossa once daily for 7 to 14 days
Alternatives:
Nystatin oral suspension 100,000 units/mL 4 to 6 mL four times daily for 7 to 14 days

MODERATE or SEVERE (See Pregnancy section below)
Fluconazole oral 100 to 200 mg once daily for 7 to 14 days

FLUCONAZOLE-REFRACTORY
Itraconazole oral solution 200 mg once daily for up to 28 days OR
Posaconazole oral suspension 400 mg twice daily for 3 days, then 400 mg daily for up to 28 days
Other options:
(no recommendations on duration, based on clinical case)
Voriconazole oral 200 mg twice daily OR
Amphotericin B oral suspension 100 mg/mL four times daily (compounded product) OR
Caspofungin IV 70 mg loading dose, then 50 mg once daily OR
Micafungin IV 100 mg daily OR
Anidulafungin IV 200 mg loading dose, then 100 mg once daily OR
Amphotericin B IV 0.3 mg/kg once daily

Occasionally tried: immunomodulation with granulocyte-macrophage colony-stimulating factor or interferon–alpha

RECURRENT
Fluconazole oral 100 mg three times weekly

PREGNANCY
When the above first-line, mild treatment options are not effective, amphotericin B (see routes/doses above) is the treatment choice during pregnancy. Systemic azoles and flucytosine should be avoided.^1,4,12,13,15 There is little data with the echinocandins, therefore caution should be taken with their use.

NOTE: Systemic azoles (including single 150 mg doses of fluconazole) should be avoided during pregnancy due to a potential for increased risk of miscarriage.^1,4,12,13,15 High doses of fluconazole (400 mg to 800 mg per day) for weeks to months during the first trimester of pregnancy have been linked to congenital malformations.^3,12,16,17

Oropharyngeal candidiasis indicates a dysfunction of the immune system and is associated with HIV infection, diabetes, leukemia and other malignancies, corticosteroid use, radiation therapy, antimicrobial use, and denture use.

Most cases are C. albicans but C. glabrata, C. dubliniensis, and C. krusei have also been reported.

Disinfection of dentures (if present) is required in addition to antifungal therapy.

Fluconazole tablets and itraconazole solution have better efficacy than ketoconazole and itraconazole capsules.

The azoles are a substrate for and inhibitors of CYP450 enzymes as well as inhibitors of P-glycoprotein.² Fluconazole has a long half-life and inhibits enzymes for 4 to 5 days after discontinuation of therapy.³

Fluconazole, voriconazole, and posaconazole are all contraindicated in patients on other drugs known to prolong the QT interval (e.g., cisapride, astemizole, erythromycin, pimozide, quinidine).^3,8-12

In fluconazole-refractory disease:

• Response rate to itraconazole is 64% to 80%.
• Response rate to posaconazole suspension is 75%.
• Typically seen in patients who are persistently immunosuppressed, such as patients with AIDS and low CD4 cell counts (<50 cells/mcL).
• Can be caused by C. glabrata.
• Resistance to fluconazole, and sometimes other azoles, is seen after prolonged or recurrent use.

HIV patients have more symptomatic relapses on topical therapy than with oral fluconazole.

Lower rates of symptomatic oropharyngeal candidiasis are seen with effective antiretroviral therapy in HIV-infected patients.

Long-term suppressive therapy with fluconazole is usually unnecessary. However, it has shown efficacy in reducing relapse rates compared to treating symptomatic episodes, but does cause development of resistance. However, there is no increase in the development of refractory disease compared to treating individual episodes. Fluconazole is more effective than oral amphotericin B, nystatin solution, or itraconazole capsules.

Vulvovaginal

NOTE: Topical antifungals refers to vaginal azoles and nystatin.

UNCOMPLICATED
Topical antifungals (no agent superior)
Alternative:
Fluconazole 150 mg oral, one dose

COMPLICATED (see Pregnancy recommendations below)
Topical antifungals for 5 to 7 days

Severe:
Fluconazole oral 150 mg every 72 hours for 2 or 3 doses

C. glabrata, unresponsive to oral azoles:
Boric acid 600 mg vaginally for 14 days (compounded product). (See Comments for more information.)
Alternative:
Nystatin vaginal suppository 100,000 units daily for 14 days OR
17% flucytosine topical cream alone or in combination with 3% amphotericin B cream daily for 14 days (compounded products)

RECURRENT
Induction:
Oral fluconazole 150 mg every 72 hours for 3 doses OR topical antifungal for 10 to 14 days^4,5,14
Maintenance:
Fluconazole oral 150 mg once weekly for at least six months

Alternatives to fluconazole for maintenance:
Clotrimazole vaginal cream 200 mg twice weekly OR
Clotrimazole vaginal suppository 500 mg once weekly OR
other intermittent oral or topical antifungals

PREGNANCY
Topical azoles for 7 days.^4,5 May use up to 14 days if required, repeating treatment if needed.¹⁸
Alternative, if necessary:
Amphotericin B vaginal suppositories (compounded) 50 mg intravaginally once a day for 14 days.⁴
Systemic azoles, including single-dose fluconazole 150 mg, should be avoided in pregnant women.^1,4,12,13,15

NOTE: Systemic azoles (including single 150 mg doses of fluconazole) should be avoided during pregnancy due to a potential for increased risk of miscarriage.^1,4,12,13,15 High doses of fluconazole (400 mg to 800 mg per day) for weeks to months during the first trimester of pregnancy have been linked to congenital malformations.^3,12,16,17

Oral fluconazole and topical antifungals are equally effective with >90% response rates.

90% of vulvovaginal candidiasis cases are uncomplicated.

Treatment is the same regardless of HIV status.

Complicated disease is defined as severe or recurrent, non-albicans species (10% to 20% of cases), during pregnancy, or infection in abnormal or compromised host (diabetes, immunocompromised, debilitated, immunosuppressive therapy)^1,4,5

Severe disease is defined by erythema, edema, excoriation, and/or fissure formation.⁴

OTC treatments (clotrimazole, miconazole, tioconazole) are often used inappropriately and can delay diagnosis and treatment of non-candidiasis vulvovaginitis cases.^5,6

C. albicans azole resistance is rare but has been reported with prolonged exposure.⁴⁴

C. krusei and C. glabrata do not respond to oral fluconazole.

Those at risk for infections with C. glabrata include those with type 2 diabetes, older age, and postmenopausal.⁶

Recurrent vulvovaginal candidiasis is defined as ≥4 episodes within one year. Once maintenance therapy is stopped, there is a 40% to 50% rate of further recurrence.

Boric Acid

• Vaginal burning reported in <10% on boric acid.⁴ Can also cause watery discharge, erythema, burning sensation.⁷
• Do not use in pregnancy due to teratogenicity and lack of safety data.^4,7 Also not recommended in lactating women.⁷
• Ensure the patient is aware that the boric acid capsules are for vaginal use NOT oral administration.
• Boric acid VAGINAL gelatin capsules (also called pessaries, suppositories) are a compounded product.
• To make, fill a #0 gelatin capsule with boric acid powder (should fit loosely), weighing the capsule to ensure it contains 600 mg of boric acid.
• There are also some OTC boric acid vaginal products on the market, however, these are generally not recommended over pharmacy-compounded capsules.

Candidemia, (Non-neutropenic)

INITIAL (See Pregnancy in Comments section)
An echinocandin:
Caspofungin IV 70 mg loading dose, then 50 mg once daily OR
Micafungin IV 100 mg once daily OR
Anidulafungin IV 200 mg loading dose, then 100 mg once daily

If not critically ill and unlikely to have fluconazole-resistant Candida species:^a
Fluconazole (po or IV): 800 mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) once daily OR
Voriconazole (po or IV) 400 mg (6 mg/kg) twice daily for two doses, then 200 mg (3 mg/kg) twice daily (as effective as fluconazole but offers little advantage)

STEP-DOWN
Switch from the echinocandin to fluconazole in 5 to 7 days if:

• Patient is clinically stable
• Isolate is susceptible to fluconazole
• Negative repeat blood culture^b

If C. glabrata is isolated and shows susceptibility:
Fluconazole (po or IV) 800 mg (12 mg/kg) once daily OR
Voriconazole (po or IV) 200 to 300 mg (3 to 4 mg/kg) twice daily

If alternatives needed because of intolerance, limited availability, or resistance:
Amphotericin B, lipid formulation IV 3 to 5 mg/kg once daily

STEP-DOWN
Switch from amphotericin B to fluconazole in 5 to 7 days if:

• Patient is clinically stable
• Isolate is susceptible to fluconazole
• Negative repeat blood culture^b

IF there is azole and echinocandin resistance:
Amphotericin B, lipid formulation IV 3 to 5 mg/kg once daily

NOTE: Systemic azoles (including single 150 mg doses of fluconazole) should be avoided during pregnancy due to a potential for increased risk of miscarriage.^1,4,12,13,15 High doses of fluconazole (400 mg to 800 mg per day) for weeks to months during the first trimester of pregnancy have been linked to congenital malformations.^3,12,16,17

Consider empiric therapy for suspected invasive candidiasis if:

• Critically ill, in the ICU
• No other known cause for fever
• Risk factors for invasive candidiasis (recent abdominal surgery, central venous catheters, parenteral nutrition, corticosteroids, dialysis, exposure to broad-spectrum antibiotics, Candida colonization, etc)

Fluconazole is renally eliminated and dose should be reduced by 50% in patients with CrCl ≤50 mL/minute who are not on dialysis. Patients on dialysis should receive the full dose of fluconazole after each dialysis.³

IV voriconazole is formulated with a cyclodextrin molecule that can accumulate in patients with significant renal dysfunction. Avoid IV voriconazole in patients with CrCl <50 mL/minute. No precaution or adjustment is needed with oral voriconazole.

Duration of therapy (if no metastatic complications):

• Two weeks after negative blood cultures^b and resolution of candidemia symptoms.
• If treatment was empiric and patient improves, give for a course of two weeks.
• If there is no clinical response to empiric treatment and no evidence of invasive candidiasis, consider stopping therapy at 4 to 5 days.

Amphotericin B is the treatment choice during pregnancy. Azoles and flucytosine should be avoided.^1,4,12,13,15 There is little data with the echinocandins, therefore caution should be taken with their use.

Better outcomes are seen with the use of early antifungals and removal of contaminated central venous catheters (if present).

Resistance varies geographically, so you need to be aware of the local epidemiology and resistance rates.

Amphotericin B is as effective as the echinocandins, but not preferred due to potential for toxicity.

Candidemia (neutropenic)

INITIAL (See Pregnancy in Comments section)
An echinocandin:
Caspofungin IV 70 mg loading dose, then 50 mg once daily OR
Micafungin IV 100 mg once daily OR
Anidulafungin IV 200 mg loading dose, then 100 mg once daily

Alternative initial therapy:
Amphotericin B, lipid formulation IV 3 to 5 mg/kg once daily
If patient is not critically ill and has had no prior azole exposure, can use:
Fluconazole (po or IV) 800 mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) once daily

STEP-DOWN
Consider if patient:

• Is clinically stable
• Has a susceptible isolate
• Has a documented negative blood culture^b

Fluconazole (po or IV) 400 mg (6 mg/kg) once daily

If additional fungi coverage is needed OR as alternate agent for step-down therapy:
Voriconazole (po or IV) 400 mg (6 mg/kg) twice daily for two doses, then 200 to 300 mg (3 to 4 mg/kg) twice daily

NOTE: Systemic azoles (including single 150 mg doses of fluconazole) should be avoided during pregnancy due to a potential for increased risk of miscarriage.^1,4,12,13,15 High doses of fluconazole (400 mg to 800 mg per day) for weeks to months during the first trimester of pregnancy have been linked to congenital malformations.^3,12,16,17

Duration of therapy (if no metastatic complications):

• Two weeks after documented clearance from the bloodstream^b and resolution of neutropenia and candidemia symptoms.

The source of candidemia in neutropenic patients is usually not a central venous catheter but rather the gastrointestinal tract. Catheters are not required to be removed and should be assessed individually.

If prolonged neutropenia is expected, granulocyte colony-stimulating factor (G-CSF)-mobilized granulocyte infusions can be considered if candidemia is persistent.

Amphotericin B is the treatment choice during pregnancy. Azoles and flucytosine should be avoided.^1,4,12,13,15 There is little data with the echinocandins, therefore caution should be taken with their use.