Prior investigations have suggested the use of a dosing weight correction factor of ideal body weight (IBW) plus 40% excess body weight (EBW, where EBW ‫؍‬ total body weight [TBW] ؊ IBW) to determine the weight to use for aminoglycoside dosing in morbidly obese (TBW/IBW ratio, >2) patients. Little data are available to provide dosing information for underweight or moderately obese patients. We investigated aminoglycoside pharmacokinetics in 1,708 patients receiving gentamicin and tobramycin. Patients were stratified into underaverage-weight or overweight weight categories based on both TBW/IBW ratio and body mass index (weight/ height 2 ratio), which has been shown to correlate with physiologic estimates of body fat. Regression analyses revealed that the TBW/IBW ratio predicts the volume of distribution. Dosing weight correction factors to give equivalent predicted peak aminoglycoside concentrations with a 2-mg/kg loading dose are 1.13 times the TBW for underweight patients and 0.43 times the EBW plus IBW for overweight patients. There were no large differences between the dosing weight correction factors derived from IBW-and body mass index-based classification systems. These data generate useful aminoglycoside dosing weight equations for both underweight and overweight patients.Ascertainment of accurate pharmacokinetic parameters for aminoglycoside dosing remains critical, as the serum drug concentration relates directly to both therapeutic response and toxic effect. Both maximum 1-h postinfusion peak and overall mean peak serum drug concentrations have been identified as significant predictors of therapeutic success for treatment of gram-negative bacteremia and pneumonia (16,17). Moore et al. demonstrated a linear dose-response effect correlating the ratio of peak serum aminoglycoside concentration/MIC to clinical response in treatment of a broad array of documented gram-negative infections (15). Deziel-Evans et al. also noted that this ratio served as an accurate determinant of response in patients treated with aminoglycosides (10). Conversely, inadequate serum drug concentrations may result in treatment failure (16,17). In addition, the narrow therapeutic effect/toxicity ratio for aminoglycosides mandates accuracy in predicting dosing parameters when attempting to reduce the risk of nephrotoxicity (4).The physiologically linked variable volume of distribution at steady state (V ss ) is an important determinant of serum drug concentration. However, V ss remains a poorly predicted pharmacokinetic parameter affecting aminoglycoside dosing in morbidly obese patients (TBW/IBW ratio Ͼ2, where TBW is total body weight and IBW is ideal body weight). This is due, in part, to the variable penetration of these highly polar polycationic compounds into adipose tissue. Additional factors influencing estimations of V ss in the population include increased projections of lean body mass and blood volume, as well as organ hypertrophy (2, 12).Past investigators have utilized dosing weight correction factors (DWCFs) to normali...

The effects of a 10-day course of moderate-dose (10 mg/kg/day) or high-dose (20 mg/kg/day) trimethoprim therapy on serum creatinine, measured creatinine clearance, urinary creatinine excretion, and serum folate were studied in 20 healthy volunteers. Serum creatinine concentrations increased significantly during trimethoprim therapy, began to decrease near day 10, and returned to baseline during the washout phase at both dosage levels. At the same time, measured creatinine clearance and urine creatinine changed in the opposite direction. No clinical or statistical differences were noted between changes in the moderate- versus the high-dose phases. Serum folate concentration decreases during high-dose trimethoprim therapy were statistically significant. Adverse drug reactions in the two groups were statistically different during the first study period, with the high-dose group having a 75% incidence rate and the moderate-dose group having an 11% incidence rate (P < 0.02). Serum creatinine, measured creatinine clearance, and urinary creatinine excretion demonstrated statistically, but not clinically, significant changes during trimethoprim therapy. In addition, high-dose trimethoprim caused significantly more adverse drug reactions than moderate-dose trimethoprim in normal volunteers.

The pharmacokinetics of oral fleroxacin were compared in men and premenopausal women. The total volume of distribution of the drug was significantly smaller in women in the single-dose trial. No difference in other pharmacokinetic parameters was noted. Since adverse events appear to occur in women more commonly than in men, dose-response studies of fleroxacin in women may be appropriate.

The pharmacokinetic parameters of gentamicin and tobramycin were evaluated and compared for 260 patients with pleural effusions and 1,049 patients without pleural effusions by chest radiograph. Pharmacokinetic data were collected prospectively and analyzed by using our aminoglycoside data base. Univariate analysis revealed that the patients with pleural effusions demonstrated significantly lower serum albumin concentrations, greater aminoglycoside volumes of distribution, longer elimination half-lives, and lower peak and higher trough concentrations in serum than the patients without pleural effusions. Patients with pleural effusions were significantly older and had lower total body weight. Stepwise multiple linear regression analysis revealed that lower total body weight and serum albumin concentration, presence of pleural effusion, and greater age were associated with significantly greater volumes of distribution. Calculated creatinine clearance, age, total body weight, and shock were associated with reduced aminoglycoside clearance in these patients.Despite the increased availability of extended-spectrum beta-lactam and fluorinated quinolone antimicrobial agents, the aminoglycosides remain an important group of antibiotics in the treatment of severe gram-negative infections (6). Individualization of aminoglycoside dosing by determining serum drug concentrations has been employed as a means of maximizing efficacy while minimizing drug toxicity (2, 13, 15). Over the past few years, however, several disease states and clinical conditions have been demonstrated to alter aminoglycoside pharmacokinetics from normally accepted parameters (4,7,14,(19)(20)(21)(22). Several authors have demonstrated that these highly polar compounds are capable of penetrating the pleural cavity and can be detected in pleural fluid (8, 9). It is possible that patients with pleural effusions possess altered pharmacokinetic parameters for aminoglycosides. The purpose of our investigation was to assess and describe the pharmacokinetics of these agents for two discrete adult populations: patients with pleural effusions demonstrable by chest radiograph and patients without pleural effusions by chest radiograph. In addition, since hypoalbuminemia has been shown to affect aminoglycoside pharmacokinetics (20), the serum albumin concentrations for these patients were examined to determine whether this nutritional deficiency was an important cofactor or whether pharmacokinetic alterations exist for patients with hypoalbuminemia.This investigation utilized data which were collected prospectively by the Clinical Pharmacy Service of The Mary Imogene Bassett Hospital from January 1983 through August 1991. Patients eligible for the study included all adult patients (ages 18 years or older) who received either gentamicin or tobramycin and who had no pathophysiology (aside from impaired renal function) known to alter aminoglycoside pharmacokinetics (4,11,19,21,22 Within 72 h of the initiation of treatment with the antibiotic, aminoglycoside pharmacokine...

Genetic transformation of murine bone marrow stem cells to methotrexate resistance was achieved using a modified calcium phosphate-DNA coprecipitation procedure. Bone marrow cells were transformed by DNA derived from methotrexate-resistant mouse 3T6 cells. In vivo selection of drug-resistant bone marrow cells resulted from thrice weekly injections of methotrexate (MTX) for a period of 6–8 wk. Following selection, dihydrofolate reductase activity encoded by the donor DNA species was easily detectable in extracts of recipient mouse spleens. In addition, selection of methotrexate-resistant cells was indicated by the persistence of spleen colony-forming units (CFU-S) in drug-treated animals. Also, changes in ratios of mixed syngeneic bone marrow cells derived from CBA and CBA/T6T6 mice resulted from initial treatment of either cell type with 3T6 DNA. These results confirm and extend the observations of Cline and coworkers that normal bone marrow cells can be genetically transformed to methotrexate resistance.