No abstract

The pharmacokinetic properties of fluconazole were studied in more than 100 pediatric patients, including 12 premature neonates. The volume of distribution and the rate of elimination differed significantly from the values reported for adults. The volume of distribution varied with age, being greatest during the neonatal period (1.18 to 2.25 l/kg) and decreasing by young adulthood to a value similar to that reported for adults (0.7 l/kg). With the exception of neonates, fluconazole clearance was generally more rapid in children than in adults, with a mean plasma elimination half-life of just over 20 h for all pediatric age groups. In neonates, fluconazole was eliminated slowly, with a mean elimination half-life of 88.6 h at birth, 67.5 h approximately one week later and 55.2 approximately two weeks after birth. Fluconazole appeared to be well absorbed from the gastrointestinal tract. These pharmacokinetic results, taken in conjunction with the corresponding data for adults, provide a sound basis for establishing appropriate fluconazole dosage recommendations for pediatric patients.

The therapeutic potential of UK-49,858, a difluorophenyl bis-triazole derivative, has been assessed by evaluating its activity against systemic infections with Candida albicans in normal mice and rats and in mice with impaired defence mechanisms, against vaginal infections with C. albicans in mice, and against dermal infections with Trichophyton mentagrophytes in guinea pigs. Orally administered ketoconazole was used as a comparative agent throughout, and parenterally administered amphotericin B was included in the study of C. albicans systemic infection in normal mice. The activity of UK-49,858 given orally to mice or rats infected systemically with C. albicans was far superior to that of ketoconazole. In addition, UK-49,858 showed activity comparable to that of amphotericin B when given parenterally, although the latter gave more prolonged protection. UK-49,858 was also effective orally in curing experimental candidal vaginitis in mice and trichophytosis in guinea pigs, against which it was approximately 10 times more active than ketoconazole. These data suggest that UK-49,858 may be of value in the treatment of both C. albicans and dermatophyte fungal infections in man.

Tioconazole (UK-20,349), a new antifungal imidazole derivative, was compared with miconazole for activity in vitro against Candida spp., Torulopsis glabrata, Cryptococcus neoformans, Aspergillus spp., and dermatophyte fungi ( Trichophyton spp. and Microsporum spp.). Tioconazole was more active than miconazole against all the fungal species examined except Aspergillus , against which both agents showed similar activity. Both tioconazole and miconazole inhibited the growth of all fungi examined at concentrations well below their quoted minimum inhibitory concentrations. Their activity against fungi in vivo was investigated in mice infected systemically with Candida albicans . Both agents significantly reduced the numbers of viable Candida cells recoverable from the kidneys of infected animals, with tioconazole producing a generally more marked reduction. After administration of a single oral dose (25 mg/kg) to beagle dogs or white mice, higher and more sustained circulating levels of bioactive drug were detectable of tioconazole than of miconazole. These observations suggest that tioconazole may have potential in the treatment of both superficial and systemic mycoses in humans.

UK-49,858 (fluconazole), a new, orally absorbed bis-triazole derivative, has been evaluated against systemic infections with Candida albicans in normal and immunosuppressed mice and against an intestinal infection with C. albicans in immunosuppressed mice. Orally administered ketoconazole was used as a comparison agent throughout, and orally administered amphotericin B was included for comparative in the experimental intestinal infection. In a 10-day dosage regimen, UK-49,858 was far more active than ketoconazole against systemic infections with C. albicans in normal and immunosuppressed mice. In normal mice, extension of UK-49,858 dosing to 30 days resulted in prolongation of survival to over 90 days, and up to 60% of treated animals had no detectable C. albicans in their kidneys. In addition, over 90% of mice with intestinal candidiasis had culture-negative feces after a 3-day treatment with UK-49,858, but only 62 and 23% of mice gave this response after amphotericin B and ketoconazole therapy, respectively. These data suggest that UK-49,858 may be of value in the treatment of systemic and gastrointestinal infections due to C. albicans in humans.The high morbidity and mortality caused by opportunistic systemic fungal infections (10, 12), their increasing incidence (2, 3), and the lack of safe, effective therapy (4, 11, 18) has prompted a search for safer and more effective drugs. UK-49,858 (fluconazole) is a new bis-triazole derivative, developed at Pfizer Ltd., which has been reported (15) to exhibit superior efficacy to that of ketoconazole in fulminating systemic candidiasis (107 CFU per animal) of normal and immunosuppressed animals as well as in superficial infections (15). Candida albicans is the most common opportunistic fungal pathogen (9,12,22), and so we have examined UK-49,858 in comparison with ketoconazole in less rapidly progressing but still lethal systemic infections (104 to 105 CFU per animal) and with ketoconazole and amphotericin B in a gastrointestinal infection in mice.MATERIALS AND METHODS Fungi. C. albicans Y0102 from the Pfizer culture collection (Pfizer Central Research, Sandwich, Kent, England) was stored freeze-dried or under liquid nitrogen, and when needed fresh cultures were grown on Sabouraud dextrose agar for 24 h at 28°C. This isolate is a standard test strain used in our laboratory and responds to azoles in a manner typical of other isolates (9, 15). Inocula for the in vivo models were prepared from washed blastospores in saline, standardized by turbidimetry with an absorptiometer (Evans Electroselenium Ltd., Halstead, England), and checked by hemocytometer counts.