Efficacy, safety and toleration of fluconazole suppositories in the treatment of oral candidosis.

An open multicentre, non-comparative study was conducted in three countries to investigate the efficacy, safety and tolerance of fluconazole suppositories in the treatment of oropharyngeal candidosis. Patients received fluconazole 100 mg day-1 in the form of suppositories or capsules. Minimum duration of total treatment was 7 days, maximum total treatment duration was 14 days, and median duration of total treatment was 9.5 (7-14) days. After having received suppository-based treatment for at least 5 days, patients could be switched to oral treatment. Eighty-two male and 19 female patients with a mean age of 43 years were enrolled in the study. The median duration of suppository treatment was 8.9 (5-14) days. Patients were evaluated clinically and mycologically at regular intervals during and at the end of treatment. Seventy-nine of 101 patients enrolled in the study were considered efficacy-evaluable. Clinical cure was achieved in 75 of 79 (95%) patients and improvement was seen in four of 79 (5%) at the end of therapy. At follow-up after 1 month, clinical cure was observed in 48 of 63 (76%) patients. The results of this study demonstrates that the fluconazole suppository formulation is effective, safe and well tolerated.

Fluconazole in the treatment of tinea corporis and tinea cruris.

BACKGROUND: Results of topical dermatomycosis treatment are often unsatisfactory, particularly in patients with extended or multiple infection sites. OBJECTIVE: Given the high fluconazole concentrations attainable in the stratum corneum and the long elimination half-life of fluconazole, we investigated whether efficacy is satisfactory when using fluconazole at once weekly doses of 150 mg. METHODS: In an open, noncomparative study, tinea corporis and cruris patients were treated with once weekly fluconazole 150 mg over 2-4 weeks. Clinical (pruritus, erythema, scaling, burning/pain, vesiculation) and mycologic (culture and microscopy) assessments were performed before treatment, at weekly intervals until the end of treatment and 3 weeks after treatment. All adverse events were recorded. RESULTS: The total severity scores of clinical symptoms were reduced from 7.1 before to 1.5 after treatment (p = 0.001, n = 100 patients). Seven patients experienced adverse events. CONCLUSIONS: Fluconazole 150 mg once weekly for 2-4 weeks is an efficacious and safe regimen in the treatment of tinea corporis and cruris.

Fluconazole concentrations in pulmonary tissue and pericardial fluid.

In order to investigate the clinical efficacy of the triazole antifungal agent fluconazole (FCA) in the treatment of pulmonary mycosis, in the present study the concentrations of fluconazole in human pulmonary tissue, pericardial fluid and serum were determined at 1, 2, 12 and 13 h after intravenous administration of fluconazole 200 mg. The mean FCA concentrations in the serum were 4.04 mg/l (1 h), 3.82 mg/l (2 h), 2.35 mg/l (12 h) and 2.13 mg/l (13 h). The respective FCA levels in the pulmonary tissue were 4.64 mg/kg, 4.54 mg/kg; 3.50 mg/kg and 3.40 mg/kg and the concentrations in the pericardial fluid were 3.86 mg/l, 3.57 mg/l, 2.35 mg/l and 2.13 mg/l. The FCA concentrations in the pulmonary tissue that were statistically significant higher than the serum concentrations were found at 2 h, 12 h and 13 h after intravenous administration (p < 0.05).

Fluconazole in the prophylaxis of fungal infection after bone marrow transplantation.

An open, non-comparative study was conducted to investigate the efficacy and safety of fluconazole in the prophylaxis of superficial or systemic fungal infections in patients having received bone marrow transplantation (BMT). The study population consisted of a total of 53 patients, including 10 children between the ages of 3 and 14 years who were scheduled for BMT. Fluconazole prophylaxis was initiated at 200 mg day-1 in adults and 100 mg day-1 in children. It was started at a mean of 7 days before treatment and continued for up to 112 days in the paediatric patients and 393 days in the adult patients. Apart from the baseline examination and the final evaluation, the patients were evaluated mycologically and serologically for the presence of fungal infections on a weekly basis, if feasible. Proven fungal infection, oesophageal candidosis or oropharyngeal candidosis was not found in any of the patients under study during the fluconazole prophylaxis. Thirteen of the adult patients developed unexplained fevers and had their treatment supplemented by antibiotic therapy and treatment with amphotericin B. In all 10 children, the prophylactic treatment proved successful. Adverse events were seen in 15 patients. In one case only, the event was judged to be causally related or possibly causally related to the study drug. Hence, fluconazole proves to be an effective and well-tolerated agent in the prophylaxis of fungal infections in recipients of bone marrow transplants.

Single-dose pharmacokinetics of fluconazole in patients with liver cirrhosis.

The pharmacokinetics of a single 100 mg i.v. dose of fluconazole were studied in parallel groups of ten normal subjects and nine patients with liver cirrhosis, a condition with a high risk of life-threatening fungal infection. The following mean pharmacokinetic parameters were found for the patient group: terminal elimination constant 0.0101/h (normal 0.0214/h); mean residence time 134 h (normal 46.7h); area under the curve 200 h.mg/L(normal 69.4 h.mg/L); plasma clearance 0.96 L/h.kg(normal 2.16 L/h.kg). All these differences were statistically significant (P < 0.05). The majority of the patients were being concomitantly treated with duretics (frusemide and spironolactone). It is suggested that the known slight interaction between such drugs and fluconazole was intensified by the disease state. These results emphasize the need for caution in the treatment with fluconazole of patients with severe liver disease. Nevertheless, in view of the wide range of values found in the patients, and low toxicity of fluconazole, a dosage reduction in cirrhosis does not seem to be justified in the present state of knowledge.

Determination of fluconazole concentrations in the prostatic and seminal vesicle fluid (split ejaculate).

The concentrations of fluconazole, a systemic antifungal agent, were determined in the split ejaculate of seven healthy volunteers. Following once-daily oral administration of fluconazole 200 mg over a period of 5 days, the fluconazole levels were determined in ejaculate samples which had been divided into two consecutive fractions upon collection. Simultaneously, a blood sample was drawn for the determination of fluconazole serum levels. It was shown that the fluconazole concentrations determined in both ejaculate fractions corresponded to those found in the serum. As the first fraction of the ejaculate originates in the prostate, the prostatic fluconazole concentrations are likely to be similar to the fluconazole levels found in th ejaculate.

The pharmacokinetics of fluconazole after a single intravenous dose in AIDS patients.

The pharmacokinetics of fluconazole after a single 100 mg i.v. dose were studied in 10 healthy subjects (5 M; 5 F) and 10 HIV-positive patients (8 M; 2 F). The mean value of plasma clearance was 25% lower in the patient groups (17 +/- 6 (s.d.) vs 23 +/- 4 ml min-1; 95% CI of difference -11 to -0.7; P < 0.05). This difference may have been related to slightly reduced kidney function in the patient group (mean creatinine clearance -18%) but is unlikely to be clinically significant. Therefore, no adjustment of the dose of intravenously administered fluconazole appears to be necessary in AIDS patients without clinical signs of enteropathy.

[Treatment of bacterial vaginitis. Multicenter, randomized, open study with tinidazole in comparison with metronidazole]. / Behandlung der bakteriellen Vaginose. Multizentrische, randomisierte, offene Studie mit Tinidazol im Vergleich zu Metronidazol.

Seventy-five patients, aged between 18 and 55, with clinical bacterial vaginosis were assigned to two treatments in a randomized fashion. One group received a single oral dose of 2 g tinidazole, the other 2 x 1 vaginal tablet of metronidazole 400 mg on five consecutive days. The clinical success rate (healing and improvement) was 97% in the group treated with tinidazole, and 84% in the group treated with metronidazole. One patient of the tinidazole group and six patients of the metronidazole group had to be given further treatment because of an inadequate response to therapy. Although there were no statistically significant differences between the two groups with respect to clinical effect and tolerance, the results do show that, for the treatment of bacterial vaginosis, a single dose of tinidazole represents a clinically effective and well-tolerated therapy that is minimally stressful for the patient and is particularly suitable for prescription by the practicing physician.

[Collection of cases in relation to clinical trials of fluconazole in Germany]. / Sammlung von Kasuistiken im Rahmen der klinischen Erprobung von Fluconazol in Deutschland.

Fluconazole is a new antifungal agent from the class of triazoles for systemic treatment of fungal infections caused by Candida or Cryptococcus. From September 1988 to June 1990, fluconazole has been made available free of charge in a clinical trial for the treatment of patients who failed to respond to conventional therapy or in whom conventional therapy was limited due to side effects etc. (compassionate usage program). Overall, 1,188 patients were entered including 79 with cryptococcal meningitis, 665 with life-threatening and 444 with non-life-threatening candidosis. The following results were found in an interim evaluation of 254 cases: The therapeutic success (cure and improvement) was 43% in patients with cryptococcal meningitis, 54% in life-threatening candidosis and 67% in non-life-threatening candidosis.

Murein biosynthesis in synchronized cells of Proteus mirabilis. Quantitative analysis of O-acetylated murein subunits and of chain terminators incorporated into the sacculus during the cell cycle.

Cells of Proteus mirabilis, synchronized by sucrose density gradient centrifugation, were grown in complex medium containing radioactive N-acetylglucosamine. At various times, labelled murein sacculi were isolated and digested with endo-N,O-acetylmuramidase from Chalaropsis. The murein fragments thus obtained were separated into disaccharide peptides as the monomeric subunits and into peptide-cross-linked subunits by gel filtration. The subunits were further differentiated into O-acetylated and non-O-acetylated species, and into subunits containing anhydro-N-acetylmuramic acid which were glycan chain terminators in the native sacculi. Quantification of the subunit species gave the following results. At specific times during the cell cycle, murein subunits were lost from the polymer and a transient decrease in cross-linkage was observed. The overall degree of cross-linkage in mature murein, i.e. the ratio of peptide-cross-linked subunits versus uncross-linked subunits, was 1.15 as determined by regression analysis. Anhydro-N-acetylmuramic-acid-containing murein subunits representing glycan chain terminators were found either peptide-cross-linked or uncross-linked as monomers. Since these two subunit species were recovered in a defined ratio of 1.6, mature murein consisted of at least two different types of glycan chains. On average, each chain contained 15.4 murein subunits. About 60% of the murein subunits in mature murein were O-acetylated and showed a higher degree of cross-linkage than the non-O-acetylated portion. Finally, following the composition of the sacculus during the cell cycle revealed a complex precursor-product relationship between non-O-acetylated and O-acetylated subunits during murein maturation. The data allowed us to deduce several features of the assembly process of murein sacculi.

Cell cycle parameters of Proteus mirabilis: interdependence of the biosynthetic cell cycle and the interdivision cycle.

We investigated the time periods of DNA replication, lateral cell wall extension, and septum formation within the cell cycle of Proteus mirabilis. Cells were cultivated under three different conditions, yielding interdivision times of approximately 55, 57, and 160 min, respectively. Synchrony was achieved by sucrose density gradient centrifugation. The time periods were estimated by division inhibition studies with cephalexin, mecillinam, and nalidixic acid. In addition, DNA replication was measured by thymidine incorporation, and murein biosynthesis was measured by incorporation of N-acetylglucosamine into sodium dodecyl sulfate-insoluble murein sacculi. At interdivision times of 55 to 57 min murein biosynthesis for reproduction of a unit cell lasted longer than the interdivision time itself, whereas DNA replication finished within 40 min. Surprisingly, inhibition of DNA replication by nalidixic acid did not inhibit the subsequent cell division but rather the one after that. Because P. mirabilis fails to express several reactions of the recA-dependent SOS functions known from Escherichia coli, the drug allowed us to determine which DNA replication period actually governed which cell division. Taken together, the results indicate that at an interdivision time of 55 to 57 min, the biosynthetic cell cycle of P. mirabilis lasts approximately 120 min. To achieve the observed interdivision time, it is necessary that two subsequent biosynthetic cell cycles be tightly interlocked. The implications of these findings for the regulation of the cell cycle are discussed.