Emergence of fluconazole-resistant strains of Candida albicans in patients with recurrent oropharyngeal candidosis and human immunodeficiency virus infection.

After repeated use of fluconazole for therapy of oropharyngeal candidosis, the emergence of in vitro fluconazole-resistant Candida albicans isolates (MIC, > or = 25 micrograms/ml) together with oral candidosis unresponsive to oral dosages of up to 400 mg of fluconazole were observed in patients with human immunodeficiency virus (HIV) infection. Antifungal susceptibility testing was done by broth microdilution and agar dilution techniques on C. albicans isolates recovered from a cohort of patients with symptomatic HIV infection who were treated repeatedly with fluconazole for oropharyngeal candidosis. In vitro findings did show a gradual increase in the MICs for C. albicans isolates recovered from selected patients with repeated episodes of oropharyngeal candidosis. Primary resistance of C. albicans to fluconazole was not seen. Cross-resistance in vitro occurred between fluconazole and other azoles (ketoconazole, itraconazole), but to a lesser extent. The results of the study suggest that the development of clinical resistance to fluconazole could be clearly correlated to in vitro resistance to fluconazole. Itraconazole may still serve as an effective antifungal agent in patients with HIV infection and oropharyngeal candidosis nonresponsive to fluconazole.

Correlation between antifungal susceptibility testing of Candida isolates from patients with HIV infection and clinical results after treatment with fluconazole.

In an open-label controlled study 23 HIV-infected patients (CDC IV A-E) with documented oropharyngeal candidosis were treated with 100 mg fluconazole orally over 5 days (53 episodes; 1-6 treatments/patient). Efficacy data were compared with a control group of 21 patients who received treatment for 10-21 days with 100 mg fluconazole for candidosis. Candida isolates were repeatedly recovered from patients before and after treatment with fluconazole and antifungal susceptibility testing (microbroth-dilution) was done. Inoculum size, medium pH, incubation time and temperature were standardized. Up to 85% of patients responded to therapy clinically and mycologically. Candida albicans was the most important yeast (86%) isolated from cultures of oral washings. In 90% of C. albicans isolates MIC to fluconazole were low (< or = 1.56 mg/l). Primary resistance to fluconazole was not seen, but secondary resistance occurred in two cases clinically and in vitro (MIC > or = 25 mg/l). Short treatment for 5 days was as successful as for 10 to 21 days without leading to significantly more recurrences of oral candidosis in these patients. Selection of Candida spp. other than C. albicans (e.g. Candida krusei, Torulopsis glabrata) under repeated fluconazole treatment occurred rarely. One patient developed clinical signs of chronic recurrent candidiasis, where only C. krusei could be cultured repeatedly.

Cytokine efficiency in the treatment of high-grade malignant non-Hodgkin's lymphomas: results of a randomized double-blind placebo-controlled study with intensified COP-BLAM +/- rhGM-CSF.

In high-grade malignant non-Hodgkin's lymphomas (hNHL) recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was evaluated as support to chemotherapy. In a phase III trial, 172 patients (age 18-73 years, stage II-IV) were risk-stratified according to LDH levels and lymphoma size and randomized to receive rhGM-CSF (400 micrograms) (87 patients) or placebo (85 patients) subcutaneously days 8-14 of each cycle of an intensified COP-BLAM regimen. RhGM-CSF significantly reduced the length and nadir of neutropenia, the length of fever episodes, the frequency of all and of severe infections, and of hospitalization and antibiotic requirements. Complete response rates were 63% for all patients and 64% vs. 61% (n.s.) in the rhGM-CSF vs. the control group. Deviations from protocol in applied dosages of myelotoxic drugs and in cycle intervals maintained differed slightly in favor of the rhGM-CSF arm. However, there were no significant differences in overall survival between the GM-CSF treatment and control groups (21 vs. 23 months). Early relapse rates were markedly lower than in the standard-dose COP-BLAM/IMVP-16 regimen. Thus, GM-CSF abates toxic side effects of chemotherapy and may help to maintain dose intensity in high-risk hNHL.

HIV-Related Lymphoblastic Lymphoma.

The clinical records of 17 patients with HIV-associated lymphoblastic mostly Burkitt-type lymphomas, are reviewed (54% of a total of 31 patients with HIV-associated malignant lymphomas, treated between 1/85-1/90). The lymphomas were diagnosed histologically with additional immuno-histochemical analyses, or cytologically, with subsequent immunocyto-chemistry. All patients were homosexual and HIV antibody positive, and the average age was 39 y. At initial staging evaluation an Ann Arbor stage III or IV was present in 15 patients (88%); a CDC-stage II of HIV-infection was present in 10 patients, CDC-stage III in 5 patients, and CDC-stage IV in 2 patients. An extranodal or mixed nodal/extranodal pattern of organ involvement was seen in 14 cases, with predominance of the gastrointestinal tract (30%) and the bone marrow (30%). The response rate to chemotherapy (CR + PR) was 81%, a CR was achieved in 53% of the patients, and relapses within a few months after CR were common. Survival following relapses in the CR- and PR group was similar, namely 5.2 and 4.9 months respectively. 2 patients in the CR-group and 1 patient in the PR group have been alive for 13, 19 and 30 months. An optimal therapeutic regimen for this disorder does not seem to have been found yet.