Renewed interest in vancomycin over the past decade has led to an abundance of data concerning the pharmacokinetics of vancomycin, and its dosage selection and concentration-response relationships. No definitive data exist that correlate vancomycin serum concentrations with clinical outcomes. However, inconsistencies in sampling times for peak serum concentrations and differences in infusion times make interpreting vancomycin serum concentrations difficult. Furthermore, the evidence implicating vancomycin as a cause of oto- or nephrotoxicity is circumstantial, and these adverse effects may occur only in high-risk populations. Owing to the variability in its dose-serum concentration relationship and multicompartmental pharmacokinetics, several methodologies have been developed for instituting and adjusting vancomycin dosages. Nomograms rely on a fixed volume of distribution and the relationship between vancomycin clearance and creatinine clearance. Since both of these factors may be altered in certain populations, dosage methodologies (both traditional and Bayesian) that use population- or patient-specific pharmacokinetic data perform better than standard nomograms for initiating vancomycin therapy. Controversy still exists as to whether a 1- or a 2-compartment model is more appropriate for making dosage adjustments; however, steady-state rather than non-steady-state vancomycin serum concentrations should be used for dosage adjustments. Certain pathophysiological states such as age, bodyweight and renal function contribute to altered pharmacokinetics and may alter the design of the dosage regimen. Since no definitive relationship exists between vancomycin serum concentrations and either clinical outcome or adverse effects, considerable controversy surrounds the utility of monitoring serum vancomycin concentrations. Therefore, routine vancomycin serum concentration monitoring may be warranted only in specific populations, such as patients receiving concurrent aminoglycoside therapy or those receiving higher than usual dosages of vancomycin, patients undergoing haemodialysis and patients with rapidly changing renal function.

OBJECTIVE -To compare the degree of insulin resistance in women with gestational diabetes mellitus (GDM) who do and do not develop preeclampsia.RESEARCH DESIGN AND METHODS -We conducted a prospective cohort study of initially normotensive women with GDM who underwent oral glucose tolerance tests (OGTTs), intravenous glucose tolerance tests (IVGTTs), and glucose clamp studies in the early third trimester (n ϭ 150) and 15 months postpartum (n ϭ 89). After delivery, the women were categorized as nonpreeclamptic or preeclamptic (systolic blood pressure [SBP] Ն140 mmHg, diastolic blood pressure [DBP] Ն90 mmHg, and at least Ͼ1ϩ proteinuria or Ͼ300 mg/24 h). Metabolic parameters between the groups were compared by 2 or Fisher's exact tests and ANOVA with P Ͻ 0.05 as significant.RESULTS -A total of 29 women (19%) developed preeclampsia, which was mild in 21 and severe in 8 women. At entry, there were no differences in age, weight indexes, and glycemic measures between the nonpreeclamptic and preeclamptic groups. Those with preeclampsia were significantly taller (61.5 Ϯ 2.4 vs. 60.1 Ϯ 2.3 in, P ϭ 0.003), were more often nulliparous (38 vs. 16%, P ϭ 0.01), and had higher entry SBP (112 Ϯ 10 vs. 103 Ϯ 6.9 mmHg, P Ͻ 0.0001) and DBP (64 Ϯ 9 vs. 59 Ϯ 5 mmHg, P ϭ 0.002). No significant differences between the groups were found in any measures of the OGTT glucose levels, insulin sensitivity index, glucose effectiveness, acute response to glucose, or disposition index, nor were there any differences found in the euglycemic clamp measures of basal or steady-state levels of glucose, insulin, free fatty acid, hepatic glucose output, peripheral glucose clearance, C-peptide, or glucagon. At 15 months postpartum, blood pressure levels remained significantly higher in the preeclamptic group (n ϭ 19) compared with the nonpreeclamptic group (n ϭ 70). No differences in any glycemic or insulin resistance measures were found.CONCLUSIONS -Women with GDM were uniformly insulin resistant. Those who developed preeclampsia, when compared with those who remained nonpreeclamptic, were not more insulin resistant in either the third trimester or 15 months postpartum. However, women who developed preeclampsia had blood pressure levels that were significantly higher, although still in the normal range, than those of women who remained nonpreeclamptic. Diabetes Care 28:1995-2000, 2005H ypertension, a common disorder complicating pregnancy (6 -9%), remains a leading cause of maternal mortality (ϳ15%) in the U.S. (1) and worldwide (2). Hypertensive disorders are increased two-to threefold in pregnancies complicated by diabetes, and insulin resistance has been proposed as an important etiologic factor (3). Women with pregestational and gestational diabetes mellitus (GDM) have been reported to have both increased risk of preeclampsia (10 -50 and 10 -30%, respectively) and insulin resistance when compared with women with normal glucose tolerance whose rate of preeclampsia is 5-7% (1-6). Several studies have reported an association between preeclampsia and i...

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Various differences in drug disposition exist between children and adults. For example, the volume of distribution (Vd) for many drugs is larger in children than in adults. Other parameters, including excretion and elimination may be altered in children compared with adults. The penicillins and cephalosporins are used commonly for the treatment of infection in paediatric patients. The increased Vd in children contributes to the increased elimination half-life of these agents. Clearance of the acylureido-penicillins is increased in children with cystic fibrosis, a disease that decreases the elimination half-life for these drugs. Aminoglycosides distribute into extracellular fluid and their pharmacokinetic profile is affected by changes in Vd. The Vd for aminoglycosides is slightly higher in children than in adults. Children with cystic fibrosis, burns, or cancer have higher clearance rates and larger Vd values for aminoglycosides. Few data in the literature address the pharmacokinetics of other anti-infective agents, including vancomycin, teicoplanin, erythromycin, metronidazole, chloramphenicol, and cotrimoxazole (trimethoprim-sulfamethoxazole), in children. Similarly, there is little information regarding the pharmacokinetic profile of antivirals and antifungals in children. Dosage guidelines are available to enable the clinician to initiate anti-infective therapy in children. Subsequent dosage requirements may change based on the patient's current clinical condition. Although several studies have investigated the pharmacokinetics of anti-infectives in neonates and adults, data for children are limited. Therefore, further studies are required so that the ever growing arsenal of anti-infectives can be administered appropriately to children.

This clinical investigation was designed to study the influence of age on stereoselective drug disposition using hexobarbital as a model marker. The disposition of hexobarbital enantiomers was investigated in 10 young and 10 elderly, healthy male volunteers. Mean oral clearance (+/- SD) of d-hexobarbital (1.9 +/- 0.5 vs. 1.7 +/- 0.3 ml/min/kg; P greater than 0.05) did not differ significantly between the young and elderly subjects, respectively. However, despite wide intersubject variability, l-hexobarbital mean oral clearance (+/- SD) was approximately twofold greater in the young than in the elderly subjects (16.9 +/- 11.9 vs. 8.2 +/- 3.2 ml/min/kg; P less than 0.05). This resulted in a significantly greater enantiomeric oral clearance ratio in the young when compared with the elderly subjects (8.3 +/- 3.4 vs. 4.7 +/- 1.4; P less than 0.01). No significant difference (P greater than 0.05) in pharmacologic response after hexobarbital administration was found between the two groups. Demonstration of an age-related preferential decline in metabolism of one enantiomer over another has not been reported previously for any racemic drug in animals or humans.

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The purpose of this clinical study was to investigate the influence of concomitant drug therapy with ciprofloxacin and rifampin on the individual pharmacokinetic profile of each agent in elderly patients. Twelve nursing home patients (age, 74 7 years), colonized with methiiillin-resistant Staphylococcus aureus, were randomized to receive 14-day therapy with oral ciprofloxacin (750 mg every 12 h) (group A; n = 6) or ciprofloxacin (750 mg every 12 h) and oral rifampin (300 mg every 12 h) (group B; n = 6). Serial blood samples were obtained from 0 to 12 h following ciprofloxacin doses 1 and 13 and from 0 to 36 h after the last ciprofloxacin dose. No significant differences (P > 0.05) were found between or within groups in any pharmacokinetic parameter. The mean ciprofloxacin oral clearance values were 0.35 ± 0.06, 0.41 ± 0.15, and 0.38 ± 0.11 liter/h per kg for doses 1, 13, and 28, respectively, in group A patients. The mean oral clearance values in group B patients for the respective doses were 0.53 ± 0.36, 0.32 ± 0.13, and 0.36 ± 0.17 liter/h per kg. Likewise, no significant differences (P > 0.05) in rifampin pharmacokinetic parameters were found when compared with historical controls. These data suggest that ciprofloxacin and rifampin may be given concomitantly in standard clinical dosing regimens. The combination results in therapeutic levels of both drugs and appears to be safe for adminiration to elderly nursing home patients.Colonization and infection with methicillin-resistant