ici-195739 and AIDS-Related-Opportunistic-Infections

We developed and compared five scoring systems designed to quantitate therapeutic response in cases of oropharyngeal candidiasis. We utilized prospectively collected data on 114 patients treated with several doses of the azole D0870. Patients were infected with fluconazole-susceptible (n = 49) or -resistant organisms (MIC, > or = 16 mg/mL; n = 61). Patients with fluconazole resistance had lower CD4+ cell counts at baseline; more symptoms (P = .0006); a higher frequency of dysgeusia (P = .004), dysphagia (P = .006), and throat pain (P = .0034); and greater oral coverage by plaques of Candida. There was no difference between the two groups in terms of colony-forming units, and any change did not correlate with response to therapy. Resolution of dysphagia (P < .01) and oral pain (P < .01) correlated well with response to therapy, unlike retrosternal pain and throat pain, which were also less frequent. Xerostomia, a "furry" taste, and dysgeusia were frequent nonspecific symptoms. Scoring system C, weighting resolution of a symptom higher than absence of a symptom at baseline, yielded the best correlation with global outcome (r = 0.86) and allows the quantitation of incomplete but clinically beneficial responses to therapy.

Topics: AIDS-Related Opportunistic Infections; Antifungal Agents; Candida albicans; Candidiasis, Oral; Colony Count, Microbial; Drug Resistance, Microbial; Esophageal Diseases; Fluconazole; Humans; Microbial Sensitivity Tests; Prospective Studies; Treatment Outcome; Triazoles

To evaluate the efficacy and tolerance of D0870 in the treatment of HIV-related fluconazole-resistant oro-oesophageal candidosis.. Multicentre open study.. HIV-seropositive patients with oro-oesophageal candidosis despite at least 7 days of treatment with fluconazole at doses of 100 mg per day or more.. Patients received an initial dose of D0870 (150 mg), then 25 mg per day for 6 days. Symptoms and signs of candidosis were compared at entry and on days 3 and 7 of treatment. At each visit, samples were taken for safety monitoring and for in vitro susceptibility testing of Candida isolates. Limited pharmacokinetic samples were taken on days 1 and 7.. Of 26 evaluable patients, 16 showed partial improvement, nine showed no improvement, and only one had full clearance of thrush by day 7. In vitro testing of the cleared patient's isolate suggested that it was susceptible to fluconazole. Symptoms of dysphagia cleared in 14 and improved in five of the 22 patients with presumptive oesophageal involvement at entry. Pharmacokinetic measurement showed wide variability in maximum D0870 levels recorded on day 1 (range, 0.07-0.34 mg/l) and susceptibility testing of isolates also showed a range of minimal inhibitory concentration values to D0870 (range, < 0.06-8 mg/l; median, 0.25 mg/l). When these data were combined with clinical response there was a strong suggestion that lack of symptomatic improvement was related to low plasma D0870 levels or to the presence of less D0870-susceptible isolates. Six patients were noted to have a fall in haemoglobin, three of whom were receiving concomitant therapy known to suppress bone marrow. Three patients reported headaches as adverse events that were attributed to study medication, but D0870 was well tolerated overall.. D0870 shows promise in the treatment of fluconazole-resistant oro-oesophageal candidosis and was well tolerated, although efficacy in this difficult-to-treat patient group was probably limited due to the inadequate plasma levels achieved in this pilot study with the low doses of D0870 administered.

Topics: AIDS-Related Opportunistic Infections; Antifungal Agents; Candida; Candida albicans; Candidiasis, Oral; Drug Resistance, Microbial; Fluconazole; Humans; Male; Microbial Sensitivity Tests; Pilot Projects; Treatment Outcome; Triazoles

This multicentre study evaluated the clinical efficacy and tolerability of D0870 in treating oropharyngeal candidiasis in HIV-positive patients who had no history of clinical resistance to fluconazole.. Three regimens were evaluated in two phases. In phase I a 50 mg initial dose was followed by 10 mg for 4 days (Group 1). In phase II a 100 mg initial dose was followed by 25 mg for 4 days (Group 2), or 10 mg for 5 days (Group 3).. Clinical cure was obtained in 27 patients of a total of 35 (77%) and six other patients improved (17%). Two patients at the lowest dose failed and both had very low plasma concentration of D0870. No association was found between clinical outcome; minimum inhibitory concentration of D0870 pre-therapy for Candida albicans, maximum recorded plasma D0870 concentration, cfu of culture or CD4 cell count at entry. Overall, 37% of the patients experienced relapse during the 2 weeks post therapy. Tolerance was excellent. Mild adverse events possibly related to the study drug were recorded in five patients.. D0870 demonstrates excellent efficacy at low doses in the treatment of HIV-related OPC and exhibits a favourable safety profile.

Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Antifungal Agents; Candida; Candida albicans; Candidiasis; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mouth Diseases; Recurrence; Treatment Outcome; Triazoles

We investigated the in vitro activity of a new antifungal triazole, D0870, against 100 Candida albicans isolates from the oral cavities of patients infected with human immunodeficiency virus by using a broth macrodilution method following the recommendations provided by the National Committee for Clinical Laboratory Standards (document M27-P). All of the isolates were chosen from C. albicans isolates already tested for fluconazole susceptibility by the procedure of the National Committee for Clinical Laboratory Standards. Fifty isolates were considered fluconazole susceptible (MICs, < or = 4 micrograms/ml), and 50 isolates were considered fluconazole resistant (MICs, > or = 8 micrograms/ml). The in vitro data demonstrated that D0870 had good activity against isolates tested; for 90% of all strains of C. albicans, MICs were 0.5 micrograms/ml. However, the D0870 MICs for the fluconazole-susceptible isolates were lower than those for the fluconazole-resistant isolates; MICs for 50 and 90% of the isolates tested were < or = 0.0078 and 0.06 micrograms/ml, respectively, for fluconazole-susceptible isolates and 0.25 and 2 micrograms/ml, respectively, for fluconazole-resistant isolates (P < 0.001). Our data suggest that this new triazole could represent a valid alternative in the treatment of oral candidiasis in human immunodeficiency virus-infected patients.

Topics: AIDS-Related Opportunistic Infections; Antifungal Agents; Candida albicans; Candidiasis, Oral; Drug Resistance, Microbial; Humans; Microbial Sensitivity Tests; Stereoisomerism; Triazoles