A comparison of once-daily and 8-hour gentamicin dosing in the treatment of postpartum endometritis.

OBJECTIVE: To evaluate whether once-daily gentamicin dosing is as effective as the traditional 8-hour regimen for the treatment of postpartum endometritis. METHODS: Postpartum women with endometritis were randomized to receive gentamicin 5 mg/kg as a single daily dose or 1.75 mg/kg every 8 hours. All subjects also received clindamycin. Each participant had a peak serum gentamicin level of at least 5.0 micrograms/mL within the first 24 hours. The dosing regimens were compared by analyzing the number of hours that patients were febrile, the length of hospital stay, occurrence of complications, pharmacy costs, and nursing time required to administer the regimens. RESULTS: The study group (n = 62) and the control group (n = 65) were similar in demographic characteristics and the presence of endometritis risk factors. No differences were found between the groups in the number of patients who completed therapy without complications, required changes in antibiotics, or required readmission for endometritis. The groups did not differ in the number of hours that patients remained febrile after the start of therapy or in the length of hospital stay. No patient in the study group had an initial peak serum concentration less than 5.0 micrograms/mL, whereas 24 patients in the control group had initial peak serum concentrations less than 5.0 micrograms/mL and required dose adjustment, a statistically significant difference (P < .001). Pharmacy costs averaged $16.12 +/- 5.68 for the study group and $41.75 +/- 17.41 for the control group, also a significant difference (P < .001). Nurse tasking time averaged 13.62 +/- 2.56 minutes for the study group and 28.06 +/- 8.77 minutes for the control group (P < .001). CONCLUSION: In patients with postpartum endometritis, once-daily gentamicin dosing provides consistently high peak serum levels of gentamicin, requires less nurse tasking time, costs less, and is as effective as the 8-hour dosing regimen.

Flow cytometric assessment of the cellular pharmacokinetics of fluorescent drugs.

Development of multidrug resistance (MDR) in cancer cells decrease net doxorubicin uptake as a result of either increased efflux, or decreased intracellular sequestration, or decreased membrane permeability. Kinetic parameters of drug uptake can distinguish among these forms of altered transport. Cellular uptake of fluorescent drugs was monitored by a flow cytometric assay using a rapid-injection system and analyzed with a three-compartment model in which rapid diffusion from extracellular fluid into the cell was followed by uptake into a nonexchangeable pool. In agreement with our recent studies of 14C-doxorubicin distribution (Dordal et al.: J Pharmacol Exp Ther 271:1286-1290, 1994), sequestration of doxorubicin was decreased 2.7-fold in P-glycoprotein-expressing SU-4R lymphoma cells compared to drug-sensitive SU-4 cells (14.0 +/- 4.8 vs. 5.0 +/- 0.9 nl s-1) without a change in membrane permeability or evidence of active efflux. In contrast, sequestration of the highly fluorescent dye rhodamine 123 was decreased 20-fold (17.1 +/- 8.3 vs. 0.9 +/- 0.8 nl s-1). Resistant cells were significantly less permeable to rhodamine than sensitive cells (3.8 +/- 1.2 vs. 10.2 +/- 2.6 x 10(5) cm2 s-1), and rhodamine efflux was increased by 24%. Thus, SU-4R cells exhibit multiple alterations that cause decreased intracellular drug concentrations, of which decreased sequestration is quantitatively the most significant.

Decreased intracellular compartmentalization of doxorubicin in cell lines expressing P-glycoprotein.

After initial rapid [14C]doxorubicin distribution into drug-sensitive HL-60 and SU-4 cells, slow uptake continues for more than 4 hr, accounting for up to 80% of the total intracellular drug. In contrast, in P-glycoprotein-expressing drug-resistant HL-60R and SU-4R cells, doxorubicin distribution rapidly approaches equilibrium. The simplest kinetic model of this behavior consists of rapid diffusion from extracellular fluid into the cell, followed by uptake into a nonexchangeable intracellular pool. At 3.4 microM doxorubicin, transmembrane diffusion clearance was similar for all cell lines (0.78-0.98 microliter sec-1). There was no decrease in the normalized apparent volume of distribution in the P-glycoprotein-expressing cell lines, as would be expected if an active, unidirectional efflux were present. However, in resistant cells, doxorubicin accumulation in the nonexchangeable pool was up to 15-fold slower than in sensitive cells (0.004 vs. 0.050 microliter sec-1 in HL-60R vs. HL-60; 0.004 vs. 0.058 microliter sec-1 in SU-4R vs. SU-4). No pool inflow could be detected in either SU-4 or SU-4R cells exposed to doxorubicin at 0 degrees C, indicating that the nonexchangeable accumulation requires energy. The process preventing accumulation began to saturate in SU-4R cells at 20 microM doxorubicin, whereas no evidence of saturation was seen with HL-60R, which is more highly resistant than SU4R. We propose that alteration in compartmentalization is primarily responsible for the doxorubicin resistance observed in these cell lines.