Fungal Infections: Candidiasis

Antifungal Prophylaxis: The results of the Community Programs for Research on AIDS (CPCRA) study of weekly fluconazole prophylaxis were reported. In this study 323 women with CD4 counts < 300/mm3 and no history of esophageal candidiasis were randomized to receive either 200 mg of fluconazole each week or placebo. The risk of oral and vaginal candidiasis was significantly reduced in the fluconazole group. There were too few episodes of esophageal candidiasis to assess any difference between the groups. There were only 13 episodes of clinical fluconazole resistance (6 in the fluconazole group, 7 in the placebo group). In vitro resistance was also rarely seen in Candida albicans isolates (5 isolates in the fluconazole group, 4 in the placebo group). Non-C. albicans species were found more frequently in the fluconazole group, but were rarely associated with clinical events. There was more frequent in vitro resistance in non-C. albicans than in C. albicans without any difference between groups. The authors concluded that weekly flu-conazole is safe and effective in reducing oral and vaginal candidiasis and that fluconazole resistance was not associated with this dosing regimen of fluconazole.

Fluconazole Resistance: Data on fluconazole resistance from an ongoing AIDS Clinical Trials Group study (ACTG 816) were also reported. This observational prospective study of mucosal candidiasis in patients with CD4 counts < 100/mm3 is investigating the incidence of fluconazole resistant candidiasis and the risk factors for the development of this disease. With clinical fluconazole failure defined as persistent mucosal candidiasis on 200 mg/d of fluconazole for 14 days, an annual incidence of fluconazole failure of 3.9% was found. Among patients taking fluconazole within the prior six months, the incidence was 4.9%. C. albicans was identified as a pathogen in the vast majority of cases of fluconazole failure. Risk factors associated with fluconazole failure included more than three episodes of thrush in the most recent 12 months, prior thrush, prior esophagitis, and any prior history of an opportunistic infection.

Data we presented from a study of Moore Clinic patients was consistent with previous observations showing that extensive prior fluconazole exposure is associated with resistance. C. albicans demonstrating in vitro resistance to fluconazole was isolated from patients entering the study taking fluconazole, whereas sensitive organisms were cultured from patients on no therapy or using topical agents. During short courses of therapy (2 - 4 weeks), however, isolates from patients treated with fluconazole showed no decline in in vitro susceptibility.

Treatment of Oral and Esophageal Candidiasis: The treatment of oropharyngeal and esophageal candidiasis was addressed in studies of itraconazole solution. Open-label itraconazole solution (200 mg/d) was compared to fluconazole (100 mg/d) and to clotrimazole (10 mg, 5 times daily) in the treatment of oropharyngeal candidiasis. Itraconazole solution for 7 or 14 days was found to show equal clinical efficacy compared to fluconazole for 14 days. Although there was a larger proportion of patients with negative cultures in those treated with itraconazole than in those treated with clotrimazole, the difference in clinical response was not statistically significant. In a third study, itraconazole solution was compared to fluconazole for the treatment of esophageal candidiasis. Patients in both groups were treated with one dose of 200 mg followed by 100 mg/d of their assigned therapy. The dose could be increased to 200 mg/d at the discretion of the investigator after one week. The proportion of patients requiring this increase in dose was not stated, but clinical and endoscopic cure rates were similar in both treatment groups.

Thus, itraconazole is an additional antifungal medication that has been shown to be effective in the treatment of oropharyngeal and esophageal candidiasis. The role of itraconazole in patients with fluconazole-resistant candidiasis remains to be clarified, as some studies have shown clinical cross-resistance between fluconazole and itraconazole, while others have reported patients with fluconazole-resistant disease that improves with itraconazole. In addition, for patients with isolated oral candidiasis, we would continue to recommend topical agents as first-line therapy in order to avoid the extensive exposure to systemic azoles that might subsequently lead to clinical and in vitro resistance.