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.

The morphology of the bone marrow of the mouse.

For an investigation on the morphology of the cells of the bone marrow of the mouse, use was made of 2 stains: MAY-GRUNWALD-GIEMSA (MGG) and methyl-green-pyronine-stilbene (MPS). The results are reported, and are compared with each other and with those obtained with the LENDRUM stain. To compare results in the same cell, its coordinates were determined with a computer-controlled scanning microscope after staining with the first method, and the preparation was then destained and restained for evaluation of the second method. The advantages and disadvantages of the stains are discussed, and it is concluded that for the evaluation of the morphology of the eosinophilic leukocyte, the MPS stain seems to be superior.

Bone-marrow eosinophilia in the mouse. I. Eosinophil leukocyte levels in untreated mice.

The number of eosinophil leukocytes in the bone marrow of untreated mice (Cpb:SE) has been shown to vary widely. A systematic investigation of this variability is reported here. The study was done a) within a group of mice, b) within groups of mice at roughly 3-month intervals, and c) within a group over a time course. The following are the most important results of this study: 1. Analysis of variance of eosinophils/1000 cells in 165 mice over a 35-day period showed that the results were consistent with the assumption that there are no changes during this interval (P is less than 0.05). 2. The number of eosinophils/1000 cells found in the various groups are not directly comparable; the mean number for the four groups investigated at intervals of about 3 months differed by a factor of up to 3. 3. On the basis of the variability found, the number of eosinophils/1000 cells in the bone marrow of a given untreated mouse in a group to be investigated cannot be reliably predicted. At a 99 per cent confidence level, the value would lie between 5 and 139.

Bone-marrow eosinophilia in the mouse. II. Eosinophil leukocyte levels in mice injected with egg-white and Freund's adjuvant.

In this article a study on the influence on bone-marrow eosinophilia in the mouse of a single injection of various concentrations of egg-white and incomplete Freund's adjuvant, together and separately, is reported. The combination of egg-white (1 per cent) and adjuvant gave a peak value of 158.3% eosinophil leukocytes on the 14th day after the injection; separately, neither one led to divergence from the results in untreated mice. The combination gave the greatest effect at 1.0 per cent and 0.1 per cent egg-white, a moderate effect with 10 per cent and 0.01 per cent, and negligible effects with 0.001 per cent. The interpretation of the results is discussed, with special attention to the relationship with the atopy syndrome in man.

Methyldibromoglutaronitrile is an important contact allergen in The Netherlands.

From 15 May to 15 December 1994, 2943 patients suspected of having contact dermatitis (1955 women, 988 men) were patch tested with methyldibromoglutaronitrile 0.3%, 0.1% and 0.05% pet. 119 patients (4.0%; women 4.1%, men 3.8%) proved to be allergic. 71% of the reactions were considered to be relevant. In 2/3 of the patients, causative products were cosmetics, in 1/3 moistened toilet tissues. Testing with methyldibromoglutaronitrile at lower concentrations (0.05% and 0.1%) and with commercial allergens (Euxyl K 400 and methyldibromoglutaronitrile, both containing methyldibromoglutaronitrile 0.1%), resulted in a number of false-negative reactions. All preservatives in the European standard series had lower scores than the 4% positive reactions to methyldibromoglutaronitrile (formaldehyde 2.0%, MCI/MI (Kathon CG) 3.2%, parabens 1.0%, quaternium-15 1.3%). It is concluded that methyldibromoglutaronitrile (present in the commercial preservative Euxyl K 400) is an important contact allergen in the Netherlands in cosmetics and moistened toilet tissues. It should be added to cosmetics series and to proctological series. The optimal test concentration is unknow, but may be 0.3% pet. The concentration of 0.1% methyldibromoglutaronitrile in the currently available commercial allergens appears to be too low, resulting in a number of false-negative reactions.