Antifungal pharmacodynamic characteristics of fluconazole and amphotericin B against Cryptococcus neoformans.

The activity of fluconazole and amphotericin B against three isolates of Cryptococcus neoformans was evaluated, with fluconazole and amphotericin B MICs of 2.0-4.0 mg/L and 1.0 mg/L respectively, using time-kill curve methods. Fluconazole was fungistatic against all isolates tested (<99.9% decrease in cfu from initial inoculum). The fungistatic activity of fluconazole was not enhanced by increasing the concentration of antifungal in solution. In contrast, amphotericin B was markedly fungicidal (> or = 99.9% decrease in cfu from initial inoculum). Both the rate and the extent of amphotericin B activity were enhanced when drug concentration was increased.

Antifungal pharmacodynamic characteristics of fluconazole and amphotericin B tested against Candida albicans.

Time-kill curves were determined for three isolates of Candida albicans tested against fluconazole and amphotericin B at multiples of the MIC. Fluconazole produced fungistatic activity, with concentration-related growth effects observed over a narrow range of concentrations. Amphotericin B exhibited fungicidal activity, with enhancement of activity over a broader range of concentrations.

Pharmacokinetics of mycophenolate mofetil and intravenous ganciclovir alone and in combination in renal transplant recipients.

STUDY OBJECTIVES: To evaluate the pharmacokinetics of mycophenolic acid and its glucuronide metabolite alone and in the presence of ganciclovir, and to determine the pharmacokinetics of ganciclovir alone and in combination with mycophenolate mofetil. DESIGN: Randomized, open-label, three-way crossover study. PATIENTS: Twelve kidney transplant recipients. INTERVENTIONS: Mycophenolate mofetil 1500 mg orally and ganciclovir 5 mg/kg intravenously were each given alone and in combination with at least a 1-week washout period between treatment arms. MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained to measure mycophenolic acid and ganciclovir by high-performance liquid chromatography. Mean (+/-SD) oral plasma clearance for mycophenolic acid alone and with ganciclovir was 3.11 +/- 0.72 and 3.19 +/- 0.72 ml/min/kg (p = 0.64). The overall disposition of the major metabolite, MPA-glucuronide, was unchanged, with approximately 70% of the administered dose eliminated as the glucuronide conjugate for both arms of the study. Mean genciclovir serum clearance was 1.80 +/- 0.58 ml/min/kg for ganciclovir and 1.70 +/- 0.55 ml/min/kg for ganciclovir plus mycophenolate mofetil (p = 0.11; 10 patients). Renal clearance of ganciclovir was decreased when the drugs were administered in combination, 1.43 +/- 0.54 (ganciclovir) and 1.26 +/- 0.44 (both drugs) ml/min/kg (p = 0.02; 10 patients). CONCLUSION: The single-dose pharmacokinetics of mycophenolic acid and its glucuronide metabolite were unchanged by the addition of ganciclovir. Total serum clearance of ganciclovir was unchanged by the addition of mycophenolate mofetil, however, renal clearance was slightly decreased.

Antifungal dynamics of LY 303366, an investigational echinocandin B analog, against Candida ssp.

Two isolates each of Candida albicans, Candida tropicalis, and Candida glabrata were selected for time-kill curve testing against LY 303366 at concentrations ranging from 0.125 x MIC to 16 x MIC. RPMI 1640 buffered morpholinepropanesulfonic acid (MOPS) was utilized as growth medium. Samples were obtained at predetermined time points over 24 hours and streaked for colony count determination. Against C. albicans (one strain) and C. glabrata isolates, LY 303366 exhibited fungicidal (> or = three log10 reduction in CFU) activity. In contrast, fungistatic activity was observed with LY 303366 against C. albicans (one strain) and C. tropicalis isolates at all of the multiples of the MIC tested. With the exception of one C. glabrata strain, the rate and extent of activity against test isolates was not enhanced with concentrations exceeding the MIC. Our data indicate that maximal antifungal activity with LY 303366 may be achieved by optimizing the time of fungal exposure to the drug. Additionally, these data suggest that use of the current interpretive endpoint for MICs in RPMI may underestimate the antifungal activity of LY 303366. Thus, the MIC endpoint may need to be re-evaluated, or perhaps an alternative media, such as antibiotic medium #3, should be utilized for determination of LY 303366 MICs.

Pharmacokinetics of F105, a human monoclonal antibody, in persons infected with human immunodeficiency virus type 1.

F105 is a human monoclonal antibody that binds to the CD4 binding site of human immunodeficiency virus type 1 gp120 and neutralizes clinical and laboratory isolates of the human immunodeficiency virus. This phase I study investigated the disposition of the antibody in humans. F105 was administered over a 60-minute period at two dose levels, 100 and 500 mg/m2. Blood samples were obtained for up to 56 days. The clearance of the antibody was 0.33 ml/min with a corresponding half-life of approximately 13 days. Peak concentrations achieved at the higher dose level were 216.19 +/- 9.62 micrograms/ml. The disposition of the drug was linear for the doses studied. Simulations were performed to design future studies aimed at investigating the efficacy of the antibody. This study concluded that F105 can be administered as a bolus dose every 21 days.