Fluconazole vs. Other Antifungals for Esophageal Candidiasis in Patients With HIV

Introduction:

Patients infected with the human immunodeficiency virus usually battle opportunistic infections as the patient's immune system is already compromised. The majority of such infections are caused by Candida Albicans, although infections caused by non-Candida Albicans species have also been reported in recent years worldwide. Esophageal candidiasis in HIV-positive patients may be the first manifestation of AIDS.

The occurrence of esophageal candidiasis acts as an indicator of immune suppression and is most often observed in patients with T lymphocyte (CD4) cell counts less than 200 cells/mm3, and the esophageal disease typically occurs at lower CD4 counts than the oropharyngeal disease.

Esophageal candidiasis is seen as an opportunistic infection in patients with HIV infection. In 1996, with the advent of highly active antiretroviral therapy (HAART), a significant decrease was noticed in the incidence of esophageal candidiasis. A variety of antifungal drugs are available for the treatment of esophageal candidiasis.

What Are the Clinical Manifestations of Esophageal Candidiasis?

Generally, esophageal candidiasis presents with retrosternal discomfort or burning pain along with painful swallowing. Sometimes, esophageal candidiasis can also be asymptomatic. Endoscopic examination reveals white plaques similar to those observed with oropharyngeal candidiasis. These plaques may occasionally progress to superficial ulcerations of the esophageal mucosa with central or peripheral whitish exudates.

The diagnosis of esophageal candidiasis is usually made based on symptoms and response to therapy. The definitive diagnosis of esophageal candidiasis is done by direct endoscopic visualization of lesions with histopathology of characteristic Candida species in tissues and is confirmed by fungal culture.

However, infection with other pathogens may result in symptoms that resemble those of esophageal candidiasis, so a diagnostic test of antifungal therapy should be performed before endoscopy.

What Are the Antifungal Drugs Used for the Treatment of Esophageal Candidiasis?

The effective treatment of esophageal candidiasis involves various systemic antifungal drugs like:

• Fluconazole.

• Clotrimazole.

• Itraconazole.

• Ketoconazole.

• Posaconazole.

• Voriconazole.

• Amphotericin B.

• Echinocandins (Caspofungin, Micafungin and Anidulafungin).

What Is the Effect of Different Drugs on Esophageal Candidiasis?

• Esophageal candidiasis has a higher relapse rate after treatment with echinocandins. Either Fluconazole (oral or intravenous) or oral Itraconazole solution is highly effective when given for 14 to 21 days. Initially, patients with severe symptoms may have difficulty swallowing oral drugs. However, Itraconazole capsules are less effective than Fluconazole because of variable absorption. Therefore, oral or intravenous Fluconazole remains the preferred therapy for esophageal candidiasis.

• The two-week course of oral Triazole isavuconazole with an initial loading dose of 200 mg, followed by 50 mg once daily, is also as effective as Fluconazole for uncomplicated esophageal candidiasis.

• Gastrointestinal adverse effects are more with a 100 mg once-daily regimen of Isavuconazole than with Fluconazole and other Isavuconazole.

• In patients who do not respond to any antifungal therapy, endoscopy is suggested to identify different causes of esophageal candidiasis or drug-resistant Candida.

What Is the Effect of Fluconazole in Comparison to Other Drugs?

• Fluconazole Versus Clotrimazole: According to the reports, available Clotrimazole is the most frequently used antifungal agent for the management of oral opportunistic infections caused in patients with HIV. However, Fluconazole has been reported to be significantly more effective than Clotrimazole in the treatment of esophageal candidiasis.

• Fluconazole Versus Itraconazole: Itraconazole was found to be as effective as Fluconazole for treating the infection. Itraconazole has also proved to be effective in the treatment of esophageal candidiasis. Patients treated with Itraconazole oral solution (100 to 200 mg/day) had clinical response rates comparable to those of patients treated with fluconazole tablets (100 to 200 mg/day). On comparing Itraconazole to Ketoconazole, Itraconazole was found to be more efficacious than Ketoconazole.

• Fluconazole Versus Ketoconazole: Oral Fluconazole is relatively safe when compared to Ketoconazole and has excellent gastric absorption. It can also be given intravenously when necessary. Studies comparing Fluconazole with either Clotrimazole or Ketoconazole demonstrate that the cure rate of Fluconazole is better than other Imidazoles. Moreover, Fluconazole has a more rapid onset of action and quicker resolution of symptoms. The comparison between Fluconazole and Ketoconazole showed that Fluconazole is superior.

• Fluconazole Versus Posaconazole: Posaconazole was also reported to be as efficacious as Fluconazole. Although, it should be noted that with Posaconazole, more patients remained asymptomatic, and very few patients had clinical relapses compared to Fluconazole.

A lack of comprehensive evidence is seen in the effectiveness and safety of antifungal agents to treat esophageal candidiasis in HIV-infected patients. Therefore, choosing the most effective intervention for the management of esophageal candidiasis in HIV (human immunodeficiency virus) infection poses a significant challenge in clinical practice.

How to Manage Treatment Failure?

The antifungal treatment is regarded as a failure if the signs or symptoms of esophageal candidiasis persist even after seven to 14 days of appropriate antifungal therapy. The refractory disease occurs in approximately four to five percent of patients with HIV infection who have esophageal candidiasis and those with a CD4 (cluster of differentiation 4) count of fewer than 50 cells/mm3. Confirmatory diagnostic culture and endoscopy in the case of esophageal candidiasis are necessary to confirm treatment failure.

In 75% of patients with Azole refractory esophageal candidiasis, immediate-release oral suspension of Posaconazole is usually effective. Alternatively, oral Itraconazole solution is effective in approximately two-thirds of patients with Fluconazole-refractory mucosal candidiasis.

Anidulafungin, Caspofungin, or Voriconazolecan be used for the treatment of Azole refractory esophageal candidiasis.

Amphotericin B can also be used for the treatment of refractory disease. Amphotericin B deoxycholate, along with the lipid preparations of Amphotericin B, has also been used. Sometimes, Amphotericin B oral suspension is effective in patients whose oropharyngeal candidiasis shows no response to Itraconazole. However, this product is not available commercially in the United States.

Conclusion:

The initial step in the management of esophageal candidiasis should always be to avoid all possible predisposing factors, such as corticosteroids, chemotherapeutic agents, and antimicrobials. Systemic antifungal therapy using oral or intravenous Fluconazole has played a major role in the treatment of esophageal candidiasis for over two decades. Fluconazole has proved to be the drug of choice for esophageal candidiasis in most patients. Topical antifungals such as Nystatin, Clotrimazole, and Miconazole play no major role in esophageal candidiasis.

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