Candida and Other Fungi

Candida spp, principally Candida albicans, are the most prevalent esophageal pathogens. When Candida is found in the normal host, a search for and correction of any predisposing factors plays an important role in both resolving the disease and preventing recurrence. Such factors include antibiotic use, inhaled or ingested corticosteroids, diabetes mellitus, malnutrition, and esophageal motility disturbances.

Therapy is highly effective for Candida esophagitis with either oral or intravenous medications. Although species other than Candida albicans cause esophagitis (eg, Candida tropicalis), speciation is not required as treatment is generally the same, regardless of species. The choice of therapy primarily depends upon the cause, severity, and expected duration of immune dysfunction. If disease is found incidentally at the time of endoscopy and the cause for candidal infection can be easily reversed (see above), no therapy may be necessary. Although nonabsorbable locally acting treatments, such as nystatin or clotrimazole troches, may be the therapy of choice for patients with disease limited to the oropharynx, systemic therapy is generally indicated for symptomatic esophageal disease. For patients with mild symptoms, minimal immunocompromise, and readily reversible immunodeficiency, a short course of a systemic agent may be given. When symptoms are more severe, an abbreviated course (7 days) of oral systemic therapy is indicated to provide more rapid symptom resolution. Immunocompromised transplant and AIDS patients

TABLE 16-1. Treatment Regimens for Common Esophageal Disease

Pathogen

Drug

Dosage

Route

Duration

Efficacy

Candida

Ketoconazole

200-400 mg/d

po

7-14 d

< 80%

Fluconazole

100 mg/d

po/IV

7-14 d

~ 80%

Itraconazole

200 mg/d

po/IV

7-14 d

~ 80%

Amphotericin B

0.5 mg/kg/d

po/IV

7d

> 95%

Caspofungin

50 mg/d

IV

7-14 d

> 90%

CMV

Ganciclovir

5 mg/kg bid

IV

2-4 wks

~ 75%

Foscarnet

90 mg/kg bid

IV

2-4 wks

~ 75%

Cidofovir

5 mg/kg weekly

IV

2-4 wks

~ 75%

Valganciclovir

900 mg bid

po

2-4 wks

-HSV

Acyclovir

400 mg 5 times/d

po/IV

14 d

> 90%

Valacyclovir

1 g tid

po

14 d

> 90%

Famciclovir

500 mg tid

po

14 d

> 90%

*Foscarnet

90 mg/kg bid

IV

14 d

> 95%

•Ganciclovir

5 mg/kg/d

IV

14 d

> 95%

Idiopathic

Prednisone

40 mg/d

PO

4 wks

> 90%

Ulcer

taper

Thalidomide

200-300 mg/d

PO

4 wks

> 90%

bid = twice daily; CMV = cytomegalovirus; HSV = herpes simplex virus; IV= intravenous; po = orally; tid = three times daily. *Same dosage as for CMV.

bid = twice daily; CMV = cytomegalovirus; HSV = herpes simplex virus; IV= intravenous; po = orally; tid = three times daily. *Same dosage as for CMV.

with Candida esophagitis should routinely be treated with systemically acting agents. Patients with granulocytopenia are at risk for disseminated candidal infection, which mandates the use of systemically acting agents as well.

Orally administered systemically active agents include ketoconazole, fluconazole, and itraconazole. Although all of these agents are effective for the treatment of Candida esophagitis, fluconazole is the drug of choice because of its excellent absorption, prolonged half-life, minimal side effects, and demonstrated superiority over both ketoconazole and itraconazole (Barbari et al, 1996). Suspension formulations of fluconazole and itraconazole are a good option when odynophagia is severe. It should be recognized that ketoconazole has a number of important drug interactions (eg, cyclosporine). Also, both ketoconazole and itraconazole require an acid milieu for absorption, which has relevance for patients with AIDS in whom hypochlorhy-dria has been observed, as well as for patients receiving proton pump inhibitors. The significantly lower cost of ketoconazole, however, warrants consideration for patients with minimal immunocompromise and minimal or mild symptoms when a short course of a systemically acting agent is preferable. A brief course of intravenous therapy (fluconazole, amphotericin B) may be required when oral intake is contraindicated or compromised.

Clinical resistance to azole therapy has been observed, and both the cumulative dose of azole and the severity of immunodeficiency have been linked to resistance. Because of the concern for resistance, generally acute treatment of symptomatic episodes should be provided instead of long term maintenance therapy. When standard doses of antifungal therapy are ineffective, drug resistance should be suspected and the dose of medication should be escalated. Some patients may require 300 to 400 mg/d or more of fluconazole to control their symptoms. When these high doses are reached, switching from flu-conazole to itraconazole should be considered. This is occcasionally helpful, but higher doses of itraconazole will also be necessary. Flucytosine has been used in combination therapy, but is ineffective as a single agent therapy, and I would not recommend its routine use. Intravenous amphotericin B is usually required when high dose (> 400 mg/d fluconazole) treatment fails. An emerging alternative here would be caspo-fungin, which also has to be given intravenously but has minimal toxicity (Arathoon et al, 2002). Immune reconstitution, when associated with improvements in CD4 T lymphocyte count, may be effective for refractory disease and provides effective secondary prophylaxis for patients with AIDS. Indeed, if significant immune reconstitution occurs with HAART, long term prophylaxis can be discontinued.

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