Pharmacokinetics and safety of tobramycin after once-daily administration in patients with cystic fibrosis.

STUDY OBJECTIVE: Tobramycin is commonly used to treat respiratory tract infections in patients with cystic fibrosis. We designed a study to determine the pharmacokinetics and safety of once-daily dosing of tobramycin in this population. DESIGN: Multiple blood samples were collected from each patient, and serum concentrations of tobramycin were determined by a fluorescence polarization immunoassay. Blood urea nitrogen and serum creatinine levels were measured every 2 to 3 days, and audiometric evaluations were performed at the start and end of therapy. MEASUREMENTS AND RESULTS: Eighteen patients (mean age, 24.6 years) received tobramycin at doses of 7 to 15 mg/kg/d as a single-dose infusion over 20 min. The maximum serum concentration of tobramycin ranged from 40.1 to 64.6 mg/L. A mean dose of 11.9+/-1.9 mg/kg was needed to obtain a theoretical mean peak serum concentration of 42.4+/-4.5 mg/L. The mean total body clearance, apparent volume of distribution, and elimination half-life was 1.7+/-0.4 mL/min/kg, 0.27+/-0.06 L/kg, and 1.8+/-0.3 h, respectively. The period of time that the serum concentration exceeded eight times the theoretical minimum inhibitory concentration of 1 mg/L ranged from 2.1 to 4.4 h, which was nearly five times longer compared with the use of divided daily doses in the same patients during previous hospitalizations. No nephrotoxicity, ototoxicity, or adverse effects occurred in any patient. CONCLUSION: Based on our data, tobramycin may be used safely in once-daily doses to treat exacerbations of respiratory tract infections in patients with cystic fibrosis.

Aerosolized dornase alpha (rhDNase) in cystic fibrosis.

Advances in the treatment and management of respiratory and pancreatic disorders has increased the life expectancy of patients with cystic fibrosis to 28 years (1). Despite the use of potent antibiotics and chest physiotherapy, persistent bacterial infection of the lung is the major cause of morbidity and mortality in these patients (2). This occurs, in part, because of the production of copious amounts of pulmonary secretions. It has been found that these secretions contain high amounts of human DNA (3-8). This high DNA concentration causes two problems. First, it increases the viscosity of sputum. This, in conjunction with reduced mucociliary clearance, decreases the removal of sputum. Second, the DNA binds to aminoglycosides, which decreases their antimicrobial efficacy (9, 10). Until recently there was no effective drug to decrease the viscosity of sputum in patients with cystic fibrosis. Dornase alpha (Pulmozyme) is the first drug to offer a safe and effective method to treat excessive DNA in sputum. In vitro studies demonstrated that rhDNase greatly decreased the viscosity of sputum by decreasing the concentration of DNA in a concentration-dependent manner (11).

Once-daily administration of aminoglycosides.

OBJECTIVE: To provide an overview of the efficacy and adverse effects associated with once-daily administration of aminoglycosides. DATA SOURCES: An extensive MEDLINE search and review of journals was conducted to identify information for this review. DATA SYNTHESIS: Aminoglycosides alone or in combination with beta-lactams are commonly used for their activity against gram-negative microorganisms. Numerous studies have been performed comparing efficacy and toxicity of once-daily administration of aminoglycosides with multiple-daily dosing. Two studies have found a significant difference in clinical efficacy between once-daily and multiple-daily dosing of aminoglycosides. Several studies have observed a lower incidence of toxicity with once-daily than multiple-daily dosing, but others have found no difference. CONCLUSIONS: Review of the literature suggests that once-daily administration of aminoglycosides may be as safe and effective as multiple-daily dosing regimens for the treatment of certain infections caused by gram-negative bacteria.

Chemically defined and serum supplemented media effects on mouse embryo development.

Mouse embryos at various stages of development were used to test three types of media: TC199, CMRL-1066 and TALP. The effect of 20% human cord serum (HCS) and fetal calf serum (FCS) were also compared in TC199 and CMRL-1066 media. Embryos were recovered at the two, four and eight cell stages and assessed for at least one cleavage progression in 24 hours. There was no difference in embryo growth rates between the media for four and eight cell embryos, however TALP significantly increased the proportion of two cell embryos which underwent at least one cleavage division. HCS significantly promoted a greater number of cleavage divisions compared with FCS. This study indicates that the defined medium (TALP) can be employed for equal or increased growth rates of early mouse embryos cultured in vitro compared to two serum supplemented media (TC199 and CMRL-1066).

Adrenal medullary hyperplasia: a clinicopathologic study of four cases.

This study presents the clinicopathologic findings in four new cases of adrenal medullary hyperplasia. The patients presented with episodic hypertension frequently associated with palpitations, headache, and diaphoresis. All four had elevated urinary catecholamine levels during attacks, and were thought clinically to have a pheochromocytoma. In each case laparotomy revealed a diffusely enlarged adrenal gland without a discrete tumor. Histologic examination of the adrenals demonstrated a diffuse and nodular expansion of the medulla confirmed by morphometric study. Of the four patients, three underwent unilateral and one bilateral adrenalectomy. Two patients who underwent unilateral adrenalectomy have been free of symptoms for three years. Thus, it would appear that adrenal medullary hyperplasia may occur unilaterally or asynchronously in the two glands. The bilaterally adrenalectomized patient has had persistent attacks, suggesting that the stimulus to adrenal medullary hyperplasia may possible affect other chromaffin tissues. On the basis of our cases and a review of the literature, we propose the following criteria for the diagnosis of adrenal medullary hyperplasia: a clinical history of episodic attacks suggesting pheochromocytoma (generally with associated increased urinary catecholamine levels), an adrenal gland showing diffuse expansion of the medulla into the alae or tail of the gland with or without nodule formation, a medulla composed of enlarged cells with or without pleomorphism, and, most important, an increased medulla/cortex ratio, together with an increased calculated medullary weight as determined by morphometric analysis.

Penetrating renal trauma in the neonate.

For years the management of blunt and penetrating renal trauma has been the source of controversy in the literature. The indications for a specific therapeutic program vary with each individual case and with the complicating factors involved. An unusual form of penetrating renal trauma in the neonate is presented and the rationale for therapy is discussed.

Neonatal necrotizing enterocolitis. Occurrence secondary to thrombosis of abdominal aorta following umbilical arterial catheterization.

A patient had neonatal necrotizing enterocolitis (NNE), secondary to aortic thrombosis following umbilical arterial catheterization. The thrombus occluded the ostium of the inferior mesenteric artery. A review of cases reported in the literature with complications following umbilical arterial catheterization revealed four instances of NNE or NNE-like lesions due to thrombosis of the abdominal aorta or one of its major branches. Thrombosis of the aorta, with occlusion of one or more of its major abdominal branches following umbilical arterial catheterization, should be considered as a potential etiologic factor in certain cases of NNE.