A phase I/II randomized, double-blind, placebo-controlled, dose-ranging study evaluating the efficacy, safety and pharmacokinetics of ravuconazole in the treatment of onychomycosis.

OBJECTIVE: To determine the effectiveness and safety of ravuconazole in the treatment of toenail onychomycosis. DESIGN: A phase I/II randomized, double-blind, double-dummy, placebo-controlled, dose-ranging study. Four 12-week dosing regimens were used: 200 mg/day; 100 mg/week; 400 mg/week and placebo. Subjects returned at weeks 2, 4, 6, 8, 10, 12, 14, 16, 24, 36 and 48 for assessment. Subjects were enrolled at 10 dermatology practices (seven in the United States, one in Canada, two in France). SUBJECTS: Adults with distal subungual onychomycosis of one great (hallux) toenail (minimum area of 25%), and at least 2 mm of proximal nail clear of disease were selected. Onychomycosis was confirmed by direct microscopy and/or fungal culture. Subjects with conditions known to produce abnormal-appearing nails were excluded. One hundred and fifty-one subjects were randomized in a 2:2:2:1 ratio to the treatments above. MAIN OUTCOME MEASURES: Primary efficacy was the effective cure rate at week 48 (mycological cure, and clinical cure or > 30% improvement). RESULTS: Effective cure was found in 56% of subjects using 200 mg/day. Effective cure was 10% in subjects receiving 100 mg/week, 8% of subjects using 400 mg/week, and 15% of subjects using placebo. Mycological cure was seen in 59% of subjects in the 200-mg/day group, which was significantly higher than the rates found in the other groups. Drug-related adverse events were infrequent in all treatment arms. Headache was the most frequently reported event. Abnormal laboratory tests were infrequent over the 12 weeks of dosing. Abnormal laboratory findings with increases beyond normal of Grade 2, 3 or 4 were found in 8/148 subjects (5.4%). Only the 200 mg daily regimen had a mean plasma steady state concentration of ravuconazole exceeding the MIC(90) adjusted for 98% protein binding (3000 ng/mL). CONCLUSIONS: For the treatment of onychomycosis, ravuconazole 200 mg/day for 12 weeks is the most effective of the regimens investigated. The safety of all regimens was acceptable. The concentrations of ravuconazole in the plasma compared to the adjusted MIC(90) may be useful in predicting the clinical and mycologic response of therapy.

Susceptibility of bacterial isolates to gatifloxacin and ciprofloxacin from clinical trials 1997-1998.

MICs of gatifloxacin and ciprofloxacin against 3482 pre-treatment, clinical trial isolates collected during 1997-1998 are reported. These data suggested that gatifloxacin was four- to eight-fold more active than ciprofloxacin against Gram-positive bacteria, with gatifloxacin MIC(90)s < or = 0.33 mg/l against Staphylococcus aureus and Streptococcus pneumoniae, and < or = 1.0 mg/l versus viridans streptococci and Enterococcus faecalis. Both quinolones had similar MIC(90)s versus Enterobacteriaceae (generally < or = 0.38 mg/l, except 0. 7-0.8 mg/l for Citrobacter freundii) and Pseudomonas aeruginosa ( approximately 8 mg/l). A total of 78% P. aeruginosa had gatifloxacin MICs < or = 2 mg/l. Gatifloxacin was more active than ciprofloxacin against Acinetobacter species and non-P. aeruginosa pseudomonads. Both had exceptional activity versus Haemophilus spp, Moraxella catarrhalis and Neisseria gonorrhoeae. In summary, compared to ciprofloxacin, gatifloxacin had improved activity against Gram-positive bacteria and comparable activity against Gram-negative bacteria.

Safety profile of cefprozil.

The clinical and laboratory safety of cefprozil was analyzed with data from 4,227 patients who received the drug in North American and European clinical efficacy trials. Of these patients, 3,016 adults and children received capsules or tablets, while 1,211 patients (mostly children) were treated with cefprozil suspension. Cefprozil was used in single-daily or twice-daily dosing regimens for treatment of infections of the upper and lower respiratory tracts, sinuses, middle ear, urinary tract, and skin and skin structure. The incidence of adverse clinical events and laboratory abnormalities was similar to that associated with use of other oral cephalosporins. Gastrointestinal adverse effects were the predominant adverse clinical event, although the incidence of diarrhea with cefprozil was much lower than that with cephalosporins that are less well absorbed. The data confirm the safety of cefprozil in both adult and pediatric patients.