The drug of choice for treating oral candidiasis in patients with compromised immune systems is Fluconazole. This is because Fluconazole is a systemic antifungal agent that provides effective and reliable oral bioavailability, allowing it to reach therapeutic concentrations in saliva and mucosal tissues.

Key points to consider:

- Fluconazole is a triazole antifungal that inhibits fungal cytochrome P450 enzyme 14α-demethylase, impairing ergosterol synthesis, which is essential for fungal cell membrane integrity.
- It has a broad spectrum of action against Candida species, including Candida albicans, the most common cause of oral candidiasis.
- Fluconazole is well tolerated and has a favorable safety profile with minimal side effects.
- It has the advantage of systemic administration, making it more effective than topical agents in immunocompromised patients where mucosal penetration and eradication are critical.
- Nystatin, although effective against oral candidiasis, is a topical agent which is less ideal for immunocompromised patients due to limited tissue penetration.
- Itraconazole and Voriconazole are other systemic azoles but are generally reserved for more resistant or invasive fungal infections and have a less favorable side effect profile or drug interaction potential for routine oral candidiasis treatment.

Therefore, Fluconazole remains the first-line therapy for oral candidiasis, especially in immunocompromised hosts such as HIV/AIDS patients, transplant recipients, or cancer patients undergoing chemotherapy.

Reference: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 9th Edition, Volume 2, Chapter 233/ Page 1947