What is the next step in treating a 2-month case of oral candidiasis (thrush) that is not responding to nystatin?

Treatment of Nystatin-Refractory Oral Thrush

Switch to oral fluconazole 100-200 mg daily for 7-14 days, as it is superior to nystatin with cure rates of 84-100% compared to nystatin's 32-51% in head-to-head trials. 1, 2, 3

First-Line Treatment for Nystatin Failure

Oral fluconazole is the definitive next step when thrush persists after 2 months of nystatin therapy. The Infectious Diseases Society of America guidelines explicitly state that fluconazole is "as effective as and in some studies superior to topical therapy" for oropharyngeal candidiasis 1. This recommendation carries the highest level of evidence (AI rating) 1.

Dosing Regimen

• Adults: Fluconazole 100 mg orally once daily for 7-14 days 1, 4
• Immunocompromised patients or severe disease: Consider 200 mg daily 4
• Continue treatment for at least 48 hours after complete symptom resolution 5

Supporting Evidence

Multiple randomized controlled trials demonstrate fluconazole's superiority:

• In immunocompromised children, fluconazole achieved 91% clinical cure versus 51% with nystatin 3
• In otherwise healthy infants, fluconazole showed 100% cure rate compared to 32% with nystatin 2
• Fluconazole provides more durable responses with better prevention of recurrence than topical agents 4

Alternative Options if Fluconazole Unavailable

If fluconazole cannot be used, itraconazole solution 200 mg daily for 7-14 days is equally efficacious 1. Note that itraconazole solution is superior to itraconazole capsules due to better absorption 1, 6.

Clotrimazole troches (10 mg five times daily for 7-14 days) are another topical alternative that may work when nystatin has failed, as they are more effective than nystatin 1, 7.

Critical Considerations Before Treatment

Rule Out Esophageal Involvement

If the patient has dysphagia, odynophagia, or retrosternal pain, esophageal candidiasis must be considered 4. This requires:

• Higher fluconazole dosing: 200-400 mg daily for 14-21 days 4
• Never use topical therapy alone for esophageal disease—it will fail completely 4

Investigate Underlying Causes

A 2-month treatment failure warrants evaluation for:

• Immunocompromised state (HIV, diabetes, corticosteroid use, chemotherapy) 1
• Denture-related disease requiring thorough denture disinfection 1
• Concomitant corticosteroid use (triamcinolone can induce nystatin resistance) 8
• Non-albicans Candida species or azole-resistant strains 1

Management of True Fluconazole-Refractory Disease

If symptoms persist after 7-14 days of fluconazole therapy:

1. Second-line: Itraconazole solution >200 mg daily (responds ~67% of the time) 1
2. Third-line: Amphotericin B oral suspension 100 mg/mL, 1 mL four times daily 1
3. Last resort: IV amphotericin B 0.3 mg/kg/day 1

Common Pitfalls to Avoid

• Do not continue nystatin indefinitely—prolonged use without response indicates treatment failure and risks developing resistance 8
• Do not assume topicals are "safer"—resistance develops with both topical and systemic therapy 4
• Do not use ketoconazole or itraconazole capsules as alternatives—they have variable absorption and are less effective than fluconazole 1
• Do not overlook dentures—denture-related candidiasis requires disinfection of the prosthesis for definitive cure 1

Suppressive Therapy Considerations

For patients with frequent or disabling recurrences, chronic suppressive therapy with fluconazole may be warranted, though this should be used judiciously to minimize resistance development 1. However, address the underlying immunocompromise (such as initiating antiretroviral therapy in HIV patients) rather than relying solely on chronic antifungals 4.