Population Pharmacokinetics of Unbound and Total Teicoplanin in Critically Ill Pediatric Patients.

BACKGROUND AND OBJECTIVES: Teicoplanin is a highly protein-bound antibiotic, increasingly used to treat serious Gram-positive infections in critically ill children. Maturational and pathophysiological intensive care unit-related changes often lead to altered pharmacokinetics. In this study, the objectives were to develop a pediatric population-pharmacokinetic model of unbound and total teicoplanin concentrations, to investigate the impact of plasma albumin levels and renal function on teicoplanin pharmacokinetics, and to evaluate the efficacy of the current weight-based dosing regimen. METHODS: An observational pharmacokinetic study was performed and blood samples were collected for quantification of unbound and total concentrations of teicoplanin after the first dose and in assumed steady-state conditions. A population-pharmacokinetic analysis was conducted using a standard sequential approach and Monte Carlo simulations were performed for a probability of target attainment analysis using previously published pharmacokinetic-pharmacodynamic targets. RESULTS: A two-compartment model with allometric scaling of pharmacokinetic parameters and non-linear plasma protein binding best described the data. Neither the inclusion of albumin nor the renal function significantly improved the model and no other covariates were supported for inclusion in the final model. The probability of target attainment analysis showed that the standard dosing regimen does not satisfactory attain the majority of the proposed targets. CONCLUSIONS: We successfully characterized the pharmacokinetics of unbound and total teicoplanin in critically ill pediatric patients. The highly variable unbound fraction of teicoplanin could not be predicted using albumin levels, which may support the use of therapeutic drug monitoring of unbound concentrations. Poor target attainment was shown for the most commonly used dosing regimen, regardless of the pharmacokinetic-pharmacodynamic target evaluated.

Autonomic dysfunction in tetanus - what lessons can be learnt with specific reference to alpha-2 agonists?

Severe tetanus is seen infrequently in the developed world, but often requires intensive care support. Mechanical ventilation with neuromuscular blockade and heavy sedation, good wound care and prompt administration of antitoxin are important. The management of autonomic dysfunction remains challenging. We measured serum catecholamine levels in a patient with severe tetanus in whom autonomic crises were a major and persistent feature, and investigated the impact of sedatives plus alpha(2)-agonists on these levels. Serum adrenaline levels were elevated up to 100-fold with clinically observed crises, although noradrenaline levels were much more difficult to interpret. There was no appreciable difference in catecholamine levels following administration of alpha(2)-agonists in the doses we used, although clonidine did allow easier control of crises with other agents. This case highlights some important lessons in the management of severe tetanus.

Effect of citrate on the urinary excretion of calcium and oxalate: relevance to calcium oxalate nephrolithiasis.

Studies in 24 recurrent oxalate stone-formers have shown that values for urinary calcium excretion for this group on at-home diets vary significantly (P less than 0.001) more than values for creatinine excretions. By placing stone-formers on controlled in-hospital diets and measuring their calcium excretions, we were able to predict probable outpatient hypercalciuria (greater than 7.5 mmol/day) with a sensitivity of 95% and a specificity of 95%. In this study, the renal loss of calcium during low-calcium diets was proportional to the absorptive hypercalciuria during high-calcium diets. Calcium loading experiments in fasted stone-formers and normal subjects indicated that citrate, at citrate:calcium molar ratios ranging from 0.12 to 1, stimulated urinary calcium excretion more than did calcium carbonate loading alone. In addition, citrate also significantly (P less than 0.05) increased the excretion of urinary oxalate by two normal subjects for a given load of calcium oxalate. Malabsorption of citrate and possibly other hydroxycarboxylic acids may thus predispose to oxalate nephrolithiasis by promoting calcium and oxalate absorption.

Two-carbon oxalogenesis compared in recurrent calcium oxalate stone formers and normal subjects.

We used a xylitol load to test the two-carbon pathway to oxalate production in humans. Use of this pentose sugar caused a fourfold increase in glycolate excretion, indicating its suitability as a dynamic function test of two-carbon metabolism. However, despite this increase in glycolate excretion in 10 recurrent stone formers and six normal subjects, there was no concomitant increase in oxalate excretion in either group. By comparison, a sucrose load produced no increase in excretion of either glycolate or oxalate. In addition, when we studied four recurrent calcium stone formers on successive diets with various fat content, we found no correlation between high fat intake and increased glycolate or oxalate excretion. In summary, there was no evidence of abnormal fluxes through the two-carbon pathway to oxalate in recurrent stone formers, nor of hyperoxaluria as related to increased intake of sucrose or fat.

Chemical factors important to calcium nephrolithiasis: evidence for impaired hydroxycarboxylic acid absorption causing hyperoxaluria.

An investigation of variables important to calcium stone formation in urine indicated significantly increased daily excretion of calcium and oxalate and decreased excretion of ascorbate and citrate by recurrent calcium stone formers. In addition, urine volume, sodium, mucopolysaccharide, and protein were also significantly increased. We compared the uptake of citrate and ascorbate from the gut into the blood in normal controls and stone formers. These studies indicated significantly depressed absorption of both these hydroxycarboxylic acids in recurrent calcium stone formers. We also found that concurrent administration of citrate inhibited ascorbate absorption and increased urinary oxalate excretion after an ascorbate load in normal subjects and stone formers. These findings suggest a mechanism that explains hyperoxaluria in stone patients on the basis of a malabsorption of citrate, ascorbate, and possibly other hydroxycarboxylic acids.

Stability of ascorbate in urine: relevance to analyses for ascorbate and oxalate.

Ascorbate is unstable in urine at room temperature at pH values ranging from 1 to 12. At pH 7 and above, oxalate is generated in amounts directly proportional to the ascorbate concentration. In 12 different urines, adjusted to pH 12 and incubated for 20 h at room temperature, there was a significant correlation between the amount of oxalate formed and the initial ascorbate concentration (r = 0.97, p less than 0.01). The mean (+/- SD) concentration of oxalate (1.32 +/- 0.70 mmol/L) formed during this period approximated the initial ascorbate concentration (1.57 +/- 1.09 mmol/L). Disodium EDTA, 10 mmol/L final concentration, stabilizes ascorbate in urine and inhibits its conversion to oxalate at pH values of 4.4 to 7.0 during a 24-h period. We therefore propose that urine specimens for ascorbate and oxalate analyses be collected with disodium EDTA present such as to give about this final concentration.