Fungal Infections: Candidiasis

Other species such as C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei may also cause symptomatic oral candidiasis in HIV-positive individuals.

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Sites of Infection:

Mucous membranes of the mouth, vagina, esophagus, GI tract, and skin.

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Diagnosis:

By visual examination, culture, or smear.

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Symptoms:

White elevated plaques of curdled appearance on mucosal epithelium. Dry mouth, altered sense of taste, oral ulcers, and difficulty swallowing.

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Treatment Results, Oropharyngeal Candidiasis (THRUSH):

Fluconazole and clotrimazole are the most commonly prescribed treatments for oral candidiasis. Other approved therapies include ketoconazole and nystatin.

Three hundred and thirty four patients with oropharyngeal candidiasis were randomized to receive fluconazole 100mg PO daily or clotrimazole 10mg PO five times daily for 14 days. Clinical response was statistically equivalent in both groups (98% of fluconazole recipients were cured or improved, vs. 94% of clotrimazole recipients). Fluconazole was more effective in eliminating C. albicans from the oral flora (65% vs. 48%) and maintaining an asymptomatic state through two weeks of follow up (82.3% vs. 50%).

In a recent report, fluconazole oral suspension was found to be superior to nystatin oral suspension for the treatment of oral candidiasis in HIV-positive patients (Pons et al.). 166 patients were randomized to receive 14 days of therapy with fluconazole 100 mg PO daily or nystatin 5 mL five times daily. 59/68 (87%) patients receiving fluconazole reported a complete clinical response, compared to 33/68 (49%) receiving nystatin (P < 0.05).

Two completed clinical trials have demonstrated itraconazole oral solution to be an effective alternative to fluconazole in treating oral and esophageal candidiasis. Graybill et al. recently treated 179 patients with itraconazole (200 mg/daily for seven days or 200 mg/daily for 14 days) or fluconazole (100 mg/daily for seven days). In the itraconazole groups, clinical cures were reported in 50/60 (83%) patients in the seven day treatment arm and 57/59 (97%) in the fourteen day treatment arm.

Frechette et al. have reported the results of a randomized, placebo-controlled study comparing fluconazole (100 mg PO daily) with two doses of oral solution itraconazole (100 mg PO bid for seven days or 100 mg/daily for 14 days) in 244 HIV-positive patients. By treatment end, 62/68 (91%) in the itraconazole groups and 7 in 8 (91%) in the fluconazole group were cured or markedly improved (P < 0.05).

De Wit et al. enrolled 37 HIV-infected patients with oropharyngeal candidiasis in a randomized, double-blind comparison of fluconazole (50 mg PO daily) and ketoconazole (200 mg PO daily) for 28 days. Clinical remission was achieved at the end of therapy in all fluconazole-treated cases and 75% of ketoconazole treated cases.

Single dose fluconazole (150 mg) may be as effective as seven days of fluconazole 50 mg for the treatment of thrush. De Wit et al. randomly treated 51 patients with either regimen and evaluated for clinical and microbiologic efficacy, tolerability and rate of relapse during a 2 week follow-up. Clinical cure was observed at day 7 in 21/24 (85%) patients treated with a single dose of fluconazole and 26/27 (96%) treated for 7 days (difference not significant).

de Repentigny et al. compared itraconazole 200 mg daily and ketoconazole 200 mg daily for the treatment of oropharyngeal or esophageal candidiasis in 128 subjects. Seventy-six patients with oropharyngeal candidiasis were treated for 14 days and 16 patients with endoscopically-proven esophageal candidiasis were treated for 28 days. No significant difference in time to clearing infection was observed between the two treatments. However, time to relapse was greater and cumulative relapse rates were lower in patients treated with itraconazole compared to ketoconazole.

Smith et al. conducted a double-blind study comparing itraconazole (200 mg PO daily) to ketoconazole (200 mg PO twice a day) in 86 HIV-positive subjects with oral or esophageal candidiasis. Clinical responses at 4 Weeks were equal for both treatments. Relapse rates were identical, with 80% of patients having a further episode of infection within three months.

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Esophageal Candidiasis:

Laine et al. conducted a randomized, double-blind study of fluconazole (100 mg PO daily) and ketoconazole (200 mg PO daily) in 169 HIV-positive patients with esophageal candidiasis. Treatment continued for two weeks after the resolution of symptoms or for a maximum of eight weeks. Clinical and endoscopic responses showed that 53/55 (96%) fluconazole-treated patients with a clinical cure also had an endoscopic cure compared to 25/44 (57%) ketoconazole-treated subjects. Side effects were minimal and comparable in the two groups.

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Fluconazole-Resistant Oropharyngeal & Esophageal Candidiasis:

Although candidiasis is usually amenable to therapy with local or systemic antifungal drugs, failures of fluconazole therapy for mucocutaneous infections due to Candida albicans have been reported. Fluconazole-refractory candidiasis occurs in 5%-10% of HIV-infected patients with low CD4+ counts who have received chronic treatment with fluconazole. Strains isolated during relapses are probably mutants of previously present susceptible strains of C. albicans (Millon et al.).

A multi-center open study of itraconazole solution (100 mg bid) for the treatment of fluconazole resistant oral candidiasis has been completed. Cartledge et al. reported a response to itraconazole solution in 16/25 patients who previously failed fluconazole. The manufacturer of itraconazole has submitted a Supplemental New Drug Application (1995) for the treatment of fluconazole-resistant oropharyngeal and esophageal candiadisis. A compassionate use program is currently underway.

Newman SL et al. reported eight cases of severe mucosal candidiasis in patients with AIDS (mean CD4+ cells counts of 15/mm³) who were taking fluconazole 400 to 800 mg per day. In both reports, intravenous amphotericin B was effective in treating fluconazole-resistant and azole cross-resistant candidiasis.

A phase II dose ranging clinical trial of oral amphotericin B for fluconazole resistant oral candidiasis is now underway (ACTG 295).

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Vaginal Candidiasis:

The most commonly recommenced treatments for vaginal candidiasis are over the counter (OTC) antifungal therapies. Treatment with topical clotrimazole or miconazole for seven days has been reported to be effective in HIV-positive women (anecdotal reports). For recurrent or persistent vaginal candidiasis oral doses of fluconazole (200 mg qd) or ketaconazole (400 mg qd) for 14 days is commonly prescribed.

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Prophylaxis of Oral & Esophageal Candidiasis:

Powderly IF et al. have reported the results of a nested study (ACTG 981) in patients previously enrolled in a larger randomized trial of primary prophylaxis for Pneumocystis carinii pneumonia. ACTG 981 was a prospective, randomized trial comparing fluconazole 200 mg PO daily to clotrimazole troches 10 mg PO five times daily for primary prophylaxis against various invasive fungal infections. A total of 428 HIV-positive patients were enrolled for a mean follow-up time of 35 months. The median CD4+ counts were 90 cells/mm³ in the fluconazole group and 114 cells/mm³ in the clotrimazole group. A total of 20 confirmed cases of esophageal candidiasis were reported; 3/217 of those receiving fluconazole and 17/211 of those receiving clotrimazole (P =0.004). There was no statistical difference in survival between the two groups.

Eighty-four subjects were enrolled into a double-blind, placebo-controlled study (Marriott et al.) of fluconazole as secondary prophylaxis for oral candidiasis. After two to four weeks of therapy with fluconazole, the patients were randomized to receive fluconazole 150 mg weekly or placebo. Of the 73 evaluable subjects, the median time to relapse was >168 days for the fluconazole group and 37 days for the placebo group.

Just-Nubling et al. conducted a randomized, open-label study of fluconazole as prophylaxis for recurrent oral candidiasis in HIV-positive subjects with CD4 count <100/mm³. 58 evaluable patients received fluconazole either 50 or 100 mg daily (observation time 137-215 days). Compared to untreated controls, fluconazole prophylaxis significantly reduced the frequency of relapse. The two fluconazole doses appeared equally effective. Other studies (Esposito et al., Stevens et al.) have shown that fluconazole (50-100 mg daily) appears to be effective in preventing recurrence of oral candidiasis in the short term (3-6 months).

Grünewaid et al. treated 69 HIV-infected individuals with CD4 <200 cells/mm³ (median = 27 cells/mm³) who had at least two prior episodes of oral or esophageal candidiasis with biweekly oral fluconazole 100 mg. After a median follow-up of 9 months, 14 of 69 subjects had developed candidiasis (7 developed oral, 5 developed esophageal and 2 developed both). Fungal cultures were performed on 30/69 patients. C. albicans was isolated from 7 of the 30 subjects.

VAGINAL CANDIDIASIS:
CPCRA 010 is a multi-center double-blind placebo-controlled study (CPCRA 010) of fluconazole for primary and secondary prophylaxis of mucosal candidiasis.

A study by Fiore et al., conducted by AmFAR's CBCT Network, demonstrated that fluconazole, is effective in preventing mucosal candidiasis in HIV-positive women. Fifty women with CD4 counts below 500/mm3 were enrolled in a randomized cross-over study to receive either fluconazole 50 mg three times weekly or no treatment with intensive monitoring for candidal infections. Mucosal candidiasis developed in 48% women who did not receive treatment an in 16% of the women receiving fluconazole (P <0.04). Multiple recurrence or candidiasis occurred in 35% who did not receive treatment and 6% in the fluconazole group (P <0.04).

Results of a study by Hilton et al. in HIV-negative women with recurrent candidal vaginitis suggests that ingestion of yogurt containing Lactobacillus acidophilus cultures decreases both candidal colonization and infection.

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REFERENCES:
Baily G et al. Fluconazole-resistant candidiasis in an HIV cohort study. AIDS 8: 787-792, 1994.

Cartledge JD et al. Itraconazole cyclodextrin solution�effective treatment for HIV-related candidiasis responsive to other azole therapy. J Anitimicrob Chemother 38:1071-1073, 1994.

de Repentigny L et al. Itraconazole vs ketaconazole in HIV-positive patients with oropharyngeal and/or esophageal candidiasis. 32nd ICAAC, Abstract 1117, 1992.

De Wit S et al. Single-dose versus 7 days of fluconazole treatment for oral candidiasis in human immunodeficiency virus-infected patients: a prospective, randomized pilot study. JID 168: 1332-3. 1993.

De Wit S et al. Comparison of fluconazole and ketoconazole for oropharyngeal candidiasis in AIDS. Lancet 1(8641): 746-8, 1989.

Esposito R et al. Maintenance therapy of oropharyngeal candidiasis in HIV-infected patients with fluconazole. AIDS 4: 1033-1034, 1990.

Fiore TC et al. Fluconazole for prophylaxis of candidal infections in women. Abstract PO-BO9-1369, IX Intl Conf AIDS, Berlin, 1993.

Frechette G et al. Effects of itraconazole in the treatment of oral candidiasis in HIV patients, a double-blind, double-dummy, randomized comparison with fluconazole. 35th ICAAC, Abstract 1219, San Francisco, 1995.

Graybill JR et al. Itraconazole oral solution versus fluconazole treatment of oropharyngeal candidiasis. 35th ICAAC, Abstract I220, San Francisco, 1995.

Grünewald TH et al. Prevention of symptomatic candidiasis with biweekly fluconazole in HIV-infected patients. 32nd ICAAC, Abstract 1116: 297, 1992.

Hilton E et al. Ingestion of yogurt containing Lactobacillus acidophilus as prophylaxis for candidal vaginitis. Ann Int Med 116: 353-357, 1992.

Just-Nubling et al. Fluconazole prophylaxis of recurrent oral candidiasis in HIV-positive patients. Eur Jour Clin Microbiol Infect Dis 10(11): 917-921, 1991.

Laine L et al. Fluconazole compared to ketaconazole for the treatment of candida esophagitis in AIDS. Ann Int Med 117: 655-660,1992.

Marriott D et al. Fluconazole once a week as a secondary prophylaxis against oropharyngeal candidiasis in HIV-infected patients. Med Jrnl Australia 158: 312-316,1993.

Millon L et al. Fluconazole-resistant recurrent oral candidiasis in human immunodeficiency virus-positive patients: persistence of Candidiasis albicans strains with the same genotype. Jrnl of Clin Micro 32(4): 1115-1118, 1994.

Newman SL et al. Fluconazole resistant mucosal candidiasis. Clin Infect Dis, in print, 1994.

Pons V et al. Comparative clinical study of oral suspension fluconazole versus topical liquid nystatin in the treatment of oropharyngeal candidiasis in AIDS. 35th ICAAC, Abstract 1221 A, San Francisco, 1995.

Pons V et al. Therapy for oropharyngeal candidiasis in HIV-infected patients: a randomized, prospective multicenter study of oral fluconazole versus clotrimazole troches. JAIDS 6:1311-6,1993.

Powderly WG et al. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. NEJM 332:700-5, 1995.

Smith DE et al. Itraconazole versus ketoconazole in the treatment of oral and esophagealcandidiasis in patients infected with HIV. AIDS 5: 1367-1371, 1991.

Stevens DA et al. Thrush can be prevented in patients with acquired immune deficiencysyndrome and acquired immune deficiency syndrome-related complex. Randomized, double-blind, placebo-controlled study of 100 mg oral fluconazole daily. Arch Intem Med 151: 2458-2464,1991.

Vecchiarelli A et al. Beneficial effect of recombinant human granulocyte colony-stimulating factor on fungicidal activity of polymorphonuclear leukocytes from patients with AIDS. Journ Infect Dis 171:448-54, 1995.

OTHER REPORTS:
Anaissie El et al. Correlation between in vitro and in vivo activity of and fungal agents against Candida species. J Infect Dis 170: 384-389, 1994.

Bailey GG et al. Fluconazole resistant candidiasis in an HIV cohort study. Abstract PO-BO9 1375, IX Intl Conf AIDS, Berlin, 1993.

Berthold P et al. Candida organisms in dental plaque from AIDS patients. J Infect Dis 170:1052-1054, 1994.

Cassone A et al. Clinical and mycological evaluation of fluconazole in the secondaryprophylaxis of esophageal candidiasis in AIDS patients. Abstract PO-BO9-1378, IX lntI Conf AIDS, Berlin, 1993.

Dismukes W et al. A randomized, double-blind trial of nystatin therapy for the candidiasishypersensitivity syndrome. NEJM 323(25): 1718.23,1990.

Horn CA et al. Azole-resistant oropharyngeal and esophageal candidiasis in patients withAIDS . AIDS 9: 5334. I995.

Puccetti P et al. Cure of murine candidiasis by recombinant soluble interleukin-4 receptor. J Infect Dis 169: 1325-1331, 1994.

Redding S et al. Resistant of Candida albicans to fluconazole during treatment of oropharyngeal candidiasis in a patient with AIDS: documentation by in vitro susceptibility testing and DNA subtype analysis. Clin Infect Dis18: 240-242,1994.

Wingard JR et al. Increase in Candida krusei infection among patients receiving bone marrow transplantation and neutropenia treated prophylactically with fluconazole. NEJM 325 (18): 1274-1277,1991.

Quart A et al. Evaluation of fluconazole in refractory oropharyngeal candidiasis in patients with AIDS. Abstract Pub 7456, VIII Intl Conf AIDS, Amsterdam, 1992.

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