Individualizing gentamicin dosage in patients with cystic fibrosis: limitations to pharmacokinetic approach

Gentamicin serum concentrations were measured in 15 children and seven adults with cystic fibrosis and in eight children with other diseases. Potentially toxic trough concentrations occurred in three of the first nine patients studied, in whom the dose and a 4-hour dosing interval were prescribed on the basis of one-compartment pharmacokinetic calculations (Sawchuck-Zaske method). In contrast, final concentrations were within the accepted target ranges for the remaining 13 patients with cystic fibrosis, in whom the dose and interval were adjusted empirically on the basis of a single pair of "peak" and trough values. The mean +/- SD final dosage required to achieve target concentrations was 13.8 +/- 2.9 mg/kg/d for children and 11.8 +/- 1.1 mg/kg/d for adults (P greater than 0.05), generally divided into four doses at 6-hour intervals. Mean half-life and incremental increase in serum concentration from previous trough to subsequent "peak," an indirect measurement of volume of distribution, were not significantly different between children or adults with cystic fibrosis and pediatric control subjects; there was little interpatient variability in these values. Thus the high dosage requirements were related more to the higher target concentrations than to altered pharmacokinetic disposition in patients with cystic fibrosis. We conclude that the initial dose of gentamicin to achieve a peak of 8 to 12 micrograms/mL and a trough of less than 2.0 micrograms/mL in patients with cystic fibrosis should be 3 mg/kg administered every 6 hours in children and every eight hours in adults. Subsequent dosage adjustment should be made on the basis of a pair of peak and trough serum concentration measurements obtained after the fifth dose. Dosing intervals in this patient population generally should be no shorter than every 6 hours, even if the initial trough concentration is less than 1 microgram/mL.     

Age-dependent dose response to gentamicin.

Serum gentamicin concentrations were measured 30 minutes after 140 intravenous doses in 60 children and nine adults with normal renal function. Distinct interpatient variation was observed but individual patients tended to have similar pharmacokinetics with repeated doses. Age had a significant effect in that mean peak serum concentrations were 1.58 mug/ml per 1 mg/kg dose in children between 6 months and 5 years, 2.03 mug/ml per 1 mg/kg in those between 5 and 10, and 2.86 mug/ml per 1 mg/kg in children 10 to 15 years of age. The mean calculated single dose of gentamicin necessary to achieve a peak serum concentration between 4 and 5 mug/ml is 2.5 mg/kg for ages 0.5 to 5 years, 2.0 mg/kg for ages 5 to 10 years, and 1.5 mg/kg for individuals over 10 years of age.     

Pharmacokinetics of enprofylline administered intravenously and as a sustained-release tablet at steady state in children with asthma

The pharmacokinetics of enprofylline (3-propylxanthine) were studied in 10 children with asthma (mean age 7.9 years), after enprofylline 1 mg/kg given intravenously and after enprofylline 7.5 +/- 1.3 mg/kg given as a sustained-release tablet after 8 days of oral dosing twice daily. The mean +/- SD enprofylline serum elimination half-life was 1.06 +/- 0.20 hours, considerably shorter than the half-life reported in adults. The mean steady-state volume of distribution was 0.55 +/- 0.05 L/kg. The mean clearance rate was 0.44 +/- 0.06 L/hr/kg. The mean enprofylline serum concentration at steady state was 1.7 +/- 0.5 mg/L. The mean peak to trough ratio was 3.02 +/- 1.31. On the first and ninth study days, 87% +/- 8% and 90% +/- 16%, respectively, of the dose of enprofylline was recovered as unchanged drug in the urine. Enprofylline has a short half-life in children, but the sustained-release formulation provides stable serum concentrations and satisfactory relief of asthma throughout the 12-hour dosing interval.     

Extended-interval gentamicin administration in malnourished children

Malnourished children have several physiologic abnormalities that can affect drug distribution and elimination. The aim of this study was to determine the efficacy, safety and pharmacokinetics of a once-daily dose of gentamicin compared with conventional thrice-daily dosing in malnourished children. To our knowledge, it has not been investigated in this population so far. A total of 310 malnourished children of either gender aged 6 months to 5 years with diarrhea and pneumonia were randomized to receive intramuscular gentamicin 5 mg/kg/day once-daily (OD) (n=148) or the same total daily amount given in three divided doses (TD) (n=162) in addition to ceftriaxone 75 mg/kg/day. After 48 h at steady state, gentamicin pharmacokinetics was assessed by fluorescence polarization immunoassay in a subgroup of 59 children and 43 children in the OD and TD groups, respectively. The groups were equivalent in baseline demographic, clinical and laboratory characteristics. Good and partial clinical responses occurred in 64 per cent vs. 54 per cent and 25 per cent vs. 27 per cent in the OD and the TD children, respectively (p=NS for both comparisons). Five patients in each treatment group died. Renal toxicity defined by change in serum creatinine was not observed in any patient from either group. In the OD group, mean+/-SD serum gentamicin concentrations at 1 (peak), 3, 5, 8, 23, and 24 (trough value) hours after the dose were 11.7+/-4.1, 4.4+/-1.2, 2.08+/-0.9, 1.01+/-0.6, 0.31+/-0.09 and 0.29+/-0.07 mg/l respectively. In the TD group, mean +/-SD serum gentamicin concentration at 1 hour (peak) was 4.7+/-1.8 mg/l and the trough concentration was 0.48+/-0.21 mg/l. In OD group, the gentamicin trough concentration was significantly lower (p<0.001) and the peak concentration was significantly higher (p<0.001) compared to TD group. The results of this study indicate that once-daily gentamicin is effective and safe in malnourished children. Widespread implementation of once-daily dosing in malnourished children is appropriate and will reduce number of intramuscular injections and hospital costs.     

Clinical and bronchodilating efficacy of controlled-release theophylline as a function of its serum concentrations in preschool children

To evaluate the dose-effect relationship of a controlled-release theophylline in preschool children, 20 patients with asthma (mean age 4.8 years, range 2 1/2 to 7 years) were given three different dose levels (13.4 +/- 1.4, 18.4 +/- 1.6, and 23.5 +/- 2.0 mg/kg/day, mean +/- SD) at 12-hour intervals for 2 weeks. Subjective variables, peak expiratory flow rate, and co-medications were recorded daily; clinical condition, serum theophylline levels, and lung function measured with a multiple forced oscillation technique were assessed at the end of each period. The morning predose (through) and 4-hour postdose (peak) serum theophylline concentrations increased in an approximately linear fashion with increasing dose. In the majority of patients, dose levels of 20 to 25 mg/kg/day maintained serum concentrations within a clinically effective range, with an acceptable level of fluctuation. However, wide interindividual variations in serum theophylline concentrations were observed, indicating that for optimal treatment individualization of dosage is preferable. Efficacy was related to serum concentration and, less closely, to the dose administered. Symptom scores for night cough, wheeze, and activity showed small improvements between 5 and 10 mg X 1(-1) and marked improvements above 10 mg X 1(-1), whereas lung function values improved in a linear fashion across the serum concentration range. The serum theophylline concentration-response curves varied in an approximately parallel manner between individuals.     

Gentamicin dosage in children

The results of 49 serum gentamicin assays from children of 2 weeks to 11 years of age are presented. The dose of gentamicin given 8-hourly intramuscularly ranged from 0-7 mg/kg-4-9 mg/kg. Doses of 1-7 mg/kg or less did not give adequate serum concentrations. As a result of these observations it is suggested that an intramuscular dose of 2-5 mg/kg given 8-hourly is suitable for most children in the absence of renal failure, but that adjustment of the dose according to serum gentamicin concentration is necessary.     

Gentamicin dosage in children.

The results of 49 serum gentamicin assays from children of 2 weeks to 11 years of age are presented. The dose of gentamicin given 8-hourly intramuscularly ranged from 0-7 mg/kg-4-9 mg/kg. Doses of 1-7 mg/kg or less did not give adequate serum concentrations. As a result of these observations it is suggested that an intramuscular dose of 2-5 mg/kg given 8-hourly is suitable for most children in the absence of renal failure, but that adjustment of the dose according to serum gentamicin concentration is necessary.     

Pharmacokinetics of levosimendan in pediatric patients evaluated for cardiac surgery.

OBJECTIVE: The objective of the study was to evaluate the pharmacokinetics, hemodynamic effects, and safety of levosimendan in children with congenital heart disease. DESIGN: Open, one group, single-dose study. SETTING: Cardiac catheter laboratory in a pediatric cardiology department of a university hospital. PATIENTS AND TREATMENTS: Thirteen children between the ages of 3 months and 7 yrs coming for preoperative cardiac catheterization were enrolled into this study. All children received 12 microg/kg levosimendan as an intravenous infusion given over 10 mins during the catheterization. MEASUREMENTS: Concentrations of levosimendan and its metabolites were determined at specified time points before and after infusion (0-4 hrs). Invasive hemodynamics was evaluated up to 25 mins after the start of the infusion and echocardiography up to 2 hrs after the start of the infusion. MAIN RESULTS: The mean maximum concentration of levosimendan was 59 +/- 23 ng/mL in children older than 6 months of age. Levosimendan was rapidly distributed, with a mean half-life of 0.24 +/- 0.07 hrs. Mean terminal elimination half-life was 1.6 +/- 0.80 hrs. Total plasma clearance for the 10-min infusion was 3.6 +/- 1.3 mL/min/kg. Terminal elimination half-life in children aged 3-6 months was slower than in older children, i.e., 2.3 hrs vs. 1.6 hrs. Values of other pharmacokinetic variables were on the same level between the two age groups. The changes in hemodynamic variables were not statistically significant. There were no serious adverse events or unexpected adverse drug reactions during the study. CONCLUSIONS: The pharmacokinetic profile of levosimendan in children with congenital heart disease is similar to that in adult patients with congestive heart failure. The minimal hemodynamic efficacy after the 12 microg/kg levosimendan bolus was probably due to a small dose relative to body surface area.     

Linear growth response to exogenous growth hormone in children with short stature

Response to growth hormone (GH) therapy was evaluated in 38 short children (28 males and 10 females; less than 1% in height for chronologic age [CA]) who were clinically categorized into three groups based on their endogenous mean 24-hour GH concentration (mean 24-hour GH) and peak GH response to two or more provocative agents (peak GH). All patients were treated with biosynthetic somatropin (human growth hormone) (0.15 to 0.30 mg/kg per week) injected subcutaneously three to seven times per week for a mean duration of 12.5 months. Group 1 consisted of 17 subjects (CA, 12.5 +/- 2.9 years [mean +/- SD]; bone age, 9.4 +/- 2.9 years; height velocity [HV], 3.4 +/- 1.8 cm/y; peak GH, 5.8 +/- 2.6 micrograms/L; mean 24-hour GH, 1.7 +/- 0.6 micrograms/L; and insulinlike growth factor-I, 0.40 +/- 0.24 U/mL. Group 2 consisted of 10 subjects (CA, 11.7 +/- 2.7 years; bone age, 9.2 +/- 3.0 years; HV, 3.4 +/- 1.6 cm/y; peak GH, 16.4 +/- 5.2 micrograms/L; mean 24-hour GH, 1.7 +/- 0.5 micrograms/L; and insulinlike growth factor-I, 0.49 +/- 0.27 U/mL. Group 3 consisted of 11 subjects (CA, 12.7 +/- 2.2 years; bone age, 10.2 +/- 2.4 years; HV, 3.5 +/- 1.5 cm/y; peak GH, 22.5 +/- 8.6 micrograms/L; mean 24-hour GH, 3.8 +/- 1.1 micrograms/L; and insulinlike growth factor-I, 1.07 +/- 0.69 U/mL. Following administration of somatropin, an increase (delta) in HV of 2.0 cm/y or greater occurred in 94% (16/17) of the group I subjects (delta HV of 5.1 +/- 2.6 cm/y), in 90% (9/10) of the group 2 subjects (delta HV of 4.3 +/- 2.2 cm/y), and in 73% (8/11) of group 3 subjects (delta HV of 3.7 +/- 2.3 cm/y). However, regardless of provoked and/or endogenous GH secretory dynamics, 88% of the children whose pretreatment HV was 2.0 cm/y or less, 94% whose pretreatment HV was between 2.0 and 4.0 cm/y, and 79% whose pretreatment HV was greater than 4.0 cm/y increased their HVs to 2.0 cm/y or greater while they were receiving somatropin. Significant negative correlations were observed between delta HV and pretreatment HV (r = -.67), delta HV and GH concentration expressed as a 24-hour area under the curve (r = -.33), and delta HV and peak GH (r = -.34).(ABSTRACT TRUNCATED AT 400 WORDS)     

Acipimox, a nicotinic acid analog, stimulates growth hormone secretion in short healthy prepubertal children

Recent studies in adult volunteers have demonstrated that the free fatty acid reduction induced by acipimox, a nicotinic acid analog, stimulated GH secretion per se and enhanced in an additive manner the GH secretion elicited by such different stimuli as pyridostigmine, GHRH and GHRP-6. In order to evaluate whether acipimox administration stimulates GH secretion in prepubertal children, we administered a single oral dose of acipimox (100 mg for children weighing <30 kg and 200 mg for those >30 kg) to 14 healthy prepubertal children with a mean age of 8.2 +/- 1.9 years, a mean bone age of 6.2 +/- 3.0 years, growing along the 5-10th percentiles, and with normal thyroid function and IGF-I levels. Acipimox administration elicited a sustained increase in GH from a mean baseline level of 0.6 +/- 0.4 to 6.7 +/- 2.4 microg/l at the end of the test (p<0.05), with a mean GH peak of 10.5 +/- 3.5 microg/l. GH release was delayed so that peak GH levels were achieved 180 minutes after acipimox administration. In order to determine whether acipimox was capable of enhancing the GH secretion elicited by levodopa (L-Dopa), we administered either oral L-Dopa (250 mg for children weighing <30 kg and 500 mg for those >30 kg) or oral acipimox plus L-Dopa to the same children on different days. GH concentrations increased in a similar fashion following either of these tests (from a baseline level of 1.2 +/- 0.4 and 0.7 +/- 0.4 microg/l to 8.4 +/- 2.7 and 9.3 +/- 2.9 microg/l at the end of the test (p<0.001), with peak GH concentrations of 13.1 +/- 4.1 and 11.8 +/- 3.3 microg/l after L-Dopa or acipimox plus L-Dopa, respectively). Although the peak GH concentrations obtained after the combined administration of acipimox plus L-Dopa were similar to those obtained after either acipimox or L-Dopa administration, a larger number of our patients reached a GH cut-off point of >7 microg/l following combined therapy than with either stimulus alone (13/14 patients with combined therapy and 10/14 with acipimox alone). No side effects other than mild facial flushing were noted after acipimox administration. These results indicate that: 1) following the administration of a single oral dose of acipimox, significant GH secretion was elicited in healthy short prepubertal children; 2) the combined administration of acipimox plus L-Dopa did not, however, enhance the GH secretion of this group of children; 3) acipimox was well tolerated with minimal side effects; and 4) further studies in both GH sufficient and GH deficient children are necessary to evaluate acipimox's usefulness in assessing GH reserve.     

The effects of galanin on growth hormone secretion in children of normal and short stature

We have evaluated the effect of galanin (Gal), a newly identified hypothalamic peptide, on growth hormone (GH) secretion in 10 children with normal stature (NS), nine with constitutional growth delay (CGD), and five with isolated GH deficiency (IGHD). Gal was infused intravenously at a rate of 8 or 15 micrograms/kg/h. All children also underwent an acute oral clonidine test (0.15 mg/m2). In CGD children the mean plasma GH peak after 8 micrograms/kg/h of Gal infusion (13.3 +/- 1.7 ng/mL; mean +/- SEM) was higher (p less than 0.02) than in NS children (8.5 +/- 0.8 ng/mL). When the dose of Gal was increased to 15 micrograms/kg/h the mean plasma GH peak in CGD children (18.5 +/- 3.5 ng/mL) was still higher than in the NS group (13.2 +/- 2.9 ng/mL), although not significantly so. In IGHD children the mean plasma GH peak elicited by 8 or 15 micrograms/kg/h of Gal (3.8 +/- 0.7 and 3.9 +/- 0.5 ng/mL, respectively) was lower than that obtained in either CGD (p less than 0.0002) or NS children (p less than 0.001). In NS children the mean plasma GH peak after acute clonidine administration (22.3 +/- 3.0 ng/mL) was higher than that observed after either dose of Gal used (p less than 0.001 and p less than 0.05 with 8 and 15 micrograms/kg/h, respectively). In CGD or IGHD children mean plasma GH peak after acute clonidine (14.8 +/- 2.6 and 4.1 +/- 1.2 ng/mL, respectively) was not significantly different from that observed after either dose of Gal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and adverse effects of amphotericin B in infants and children

The pharmacokinetics and safety of amphotericin B infusion were studied in 13 infants and children (age range 3 weeks to 18 years; median age 11 years) treated with the drug for proved (n = 11) or suspected (n = 2) fungal infections. The dose during the first day was 0.5 mg/kg, followed by a daily dose of 1 mg/kg for the rest of the treatment period in most patients. The drug was infused over 4 to 6 hours. During the first day, serum concentrations were above the target therapeutic level of 0.3 microgram/ml in all patients at 2 and 6 hours from the start of the infusion, in 12 of 13 patients at 12 hours, but in only 6 of 13 patients at 24 hours. On the third day, all concentrations were greater than 0.3 microgram/ml throughout the 24-hour period, and in 12 of 13 patients were greater than 0.5 microgram/ml. The same kinetic profile prevailed on days 7 to 10 of therapy, with a tendency for increasing concentrations. Elimination half-life was 9.93 +/- 1.5 hours (mean +/- SEM), clearance rate 26 +/- 5 ml/kg.hr, and distribution volume 378 +/- 25 ml/kg. The half-life inversely correlated with patient's age. Pharmacokinetic values calculated during the first day were not different from those calculated on day 3. Significant decreases in hemoglobin, platelets, and serum potassium concentration were recorded along with significant increases in serum creatinine, urea, and aspartate transaminase values. Because of the large pharmacokinetic variability and the high rate of serious adverse effects, individualized dosing of amphotericin B based on therapeutic drug monitoring should be considered.     

Study of intermittent intravenous deferrioxamine high-dose therapy in heavily iron-loaded children with beta-thalassemia major poorly compliant to subcutaneous injections

The authors tested the efficacy and safety of intermittent high doses of iv deferrioxamine (DFX) on a twice-weekly basis through an externalized venous catheter on 14 thalassemic children who were heavily iron-loaded and poorly or noncomplaint to subcutaneous DFX. The main reasons for their noncompliance were resistance of the child because of severe local reactions or more than one family member affected, with very high burden on the mother to look after all the affected children. There were 9 males and 5 females and their age range was 7-13 years (mean 10.93 +/- 1.9 years). All patients were given a 48-h continuous iv infusion of DFX 200-240 mg/kg/day (approximately 10 mg/kg/h) every 2 weeks, combined with subcutaneous 10-h infusion of DFX 3 days/week. One month after the start of the intermittent high-dose DFX program, the 24 h urinary iron excretion was 29.1-1.50 mg/kg/24 h (mean 69.7 +/- 32.5 mg/kg/24 h). These values dropped significantly to 29-53 mg/kg/24 h (mean 39.8 +/- 7.9 mg/kg/24 h) 1 year after the study (p <.004) and remained almost the same over the second year (mean 39.07 +/- 6.58 mg/kg/24 h). Serum ferritin levels markedly elevated before the start of high-dose chelation fell steadily during iv high-dose DFX therapy. Mean values were 6215.5 +/- 578.3, 3971.5 +/- 321.6, 2507.2 +/- 131.2, and 1866.5 +/- 110 ng/mL at 0, 6, 12, and 24 months, respectively. No serious side effects were reported. Intermittent high-dose DFX therapy combined with 3 days of subcutaneous DFX is safe and effective in reducing iron stores and improving the compliance of these heavily iron-loaded thalassemic children.     

Pharmacokinetic and pharmacodynamic study of midazolam in children during esophagogastroduodenoscopy

We undertook a prospective study to evaluate the relationship between the onset and degree of sedation and the midazolam plasma concentration in children between 6 and 18 years of age during esophagogastroduodenoscopy. Thirteen boys and seven girls (median age 13.5 years) were studied. Midazolam was injected intravenously for 5 minutes, and the dose was titrated to sedation or a maximum dose of 0.1 mg/kg was given. Plasma midazolam concentration was determined just before and at 5, 10, 15, 30, 45, and 60 minutes after the start of midazolam injection. The patient's level of sedation was evaluated by an assistant at each blood sampling time. Clearance, volume of distribution, and terminal elimination (beta) half-life were estimated from a biexponential fit of the serial plasma midazolam concentrations. Mean beta half-life of midazolam was 47 +/- 26 minutes and mean clearance was 10.0 +/- 5.0 ml/min per kilogram of body weight. Maximum level of sedation occurred at 5 minutes after initiation of the injection and corresponded to a mean peak midazolam serum concentration of 229 +/- 39 micrograms/L. Thereafter, a decline of mean sedation scores paralleled the decrease in midazolam concentration. Mean oxygen saturation remained greater than 94% during the study. We conclude that children metabolize and excrete midazolam more rapidly than adults do and that sedation adequate for endoscopy is safely achieved in the majority of children with a midazolam dose of 0.05 to 0.1 mg/kg and a mean peak midazolam concentration greater than 200 microgram/L.     

Noradrenaline for management of septic shock refractory to fluid loading and dopamine or dobutamine in full-term newborn infants

AIM: To determine the effects of noradrenaline in full-term newborns with refractory septic shock. METHODS: Newborns of >35 weeks' gestation with persistent septic shock, despite adequate fluid resuscitation and high dose of dopamine/dobutamine were eligible. In this prospective observational study, we recorded respiratory and hemodynamic parameters prior to and 3 h after starting noradrenaline infusion. RESULTS: Twenty-two newborns were included (gestational age [GA] 39 +/- 1.7 weeks, birth weight (BW) 3110 +/- 780 g). Before starting noradrenaline, the infants received a mean volume expansion of 31 +/- 15 mL/kg and a mean infusion rate of dopamine of 14 +/- 5 microg/kg/min or dobutamine of 12 +/- 6 microg/kg/min. Three hours after starting noradrenaline (rate 0.5 +/- 0.4 microg/kg/min), the mean arterial blood pressure rose from 36 +/- 5 to 51 +/- 7 mmHg (p < 0.001). Urine output increased from 1 +/- 0.5 to 1.7 +/- 0.4 mL/kg/h (p < 0.05). Blood lactate concentration decreased from 4.8 +/- 2.3 to 3.3 +/- 1.8 mmol/L (p < 0.01). Despite an initial correction of hypotension, four infants died later. CONCLUSION: Noradrenaline was effective in increasing systemic blood pressure. An increase in urine output and a decrease in blood lactate concentration suggest that noradrenaline may have improved cardiac function and tissue perfusion.     

Multiple dose pharmacokinetics of ciprofloxacin in preterm babies

BACKGROUND: Ciprofloxacin is increasingly used in preterm neonates to treat multi-drug resistant infections, however the pharmacokinetics of this drug in preterm newborns is not well studied. OBJECTIVES: To determine the multi-dose pharmacokinetics of intravenous ciprofloxacin in pre-term infants. DESIGN: Prospective, cohort study. SETTING: Level III Neonatal Intensive Care Unit in a tertiary Care hospital in North India. METHODS: 24 preterm neonates with age < 28 days, who received intravenous ciprofloxacin 10 mg/kg/dose 12 hourly for clinical and/or culture proven sepsis, were enrolled. Serum levels of ciprofloxacin were analyzed after first dose on day 1 and at the end of days 3 and 7. Results: Of 24 babies included in the study [mean gestation (SD) 32 wks (2.4 wks)], 3 died and 1 dropped out in the initial few days, leaving 20 patients whose data on serum ciprofloxacin were available. Peak values on days 1, 3 and 7 were [mean +/- SEM] 2.3 +/- 0.39 microg/mL, 3.0 +/- 0.44 microg/mL and 2.7 +/- 0.39 microg/mL respectively (P >0.05). Trough values on these days were 0.7 +/- 0.14 microg/mL 0.8 +/- 0.14 microg/mL and 1.0 +/- 0.21 microg/mL respectively (P > 0.05). There were no differences between the <1500 g and > 1500 g sub-groups and the < 7 days and >7 days sub-groups with respect to the corresponding peak and trough values on days 1, 3 and 7. The 95% C.I. of serum concentrations were above the MIC90 for most Enterobacteriaceae species, however the lower bound of the 95% C.I. of the mean trough levels was lower than MIC90 for Pseudomonas aeruginosa and Staphylococcus aureus. No adverse effects were observed. CONCLUSIONS: Intravenous ciprofloxacin in a dose of 10 mg/kg/dose 12 hourly is an effective treatment of neonatal sepsis, but higher doses may be required for treating Staphylococcus aureus and Pseudomonas.     

Pharmacokinetics and antipruritic effects of hydroxyzine in children with atopic dermatitis

We studied the pharmacokinetics and antipruritic effects of hydroxyzine hydrochloride in 12 children, mean age 6.1 +/- 4.6 years, with severe atopic dermatitis. After a single 0.7 mg/kg orally administered dose of the drug, the mean peak serum hydroxyzine concentration of 47.4 +/- 17.3 ng/ml occurred at a mean time of 2.0 +/- 0.9 hours. The mean elimination half-life was 7.1 +/- 2.3 hours, the mean clearance rate was 32.08 +/- 11.05 ml/min/kg, and the mean apparent volume of distribution was 18.5 +/- 8.6 L/kg. The elimination half-life increased with increasing age (r = 0.83). Pruritus was significantly suppressed from 1 to 24 hours after the administration of the dose, with greater than 85% suppression from 2 to 12 hours. The only adverse effect reported was sedation. In a subsequent double-blind, crossover, multiple-dose study of 2 weeks' duration, hydroxyzine 0.7 mg/kg three times daily was as effective as hydroxyzine 1.4 mg/kg three times daily in relieving pruritus and promoting resolution of the skin lesions. The 0.7 mg/kg tid dose caused significantly less sedation than the 1.4 mg/kg tid dose.     

Pharmacokinetics of intravenously administered azithromycin in pediatric patients

BACKGROUND: The objective of this study was to characterize the pharmacokinetics and tolerance of a single intravenous (IV) azithromycin dose in children. METHODS: Subjects were stratified into 4 age groups: 0.5-2 years; >2-<6 years; 6-<12 years; and 12-<16 years. Each subject received a single 10 mg/kg dose (500 mg maximum) infused in 1 hour. Serial venous blood samples were obtained for a 168-hour period, and laboratory safety evaluations were performed immediately preceding azithromycin administration and at the conclusion of the study. Serum azithromycin concentrations were quantified with a validated high performance liquid chromatography method with mass spectrometric detection. Pharmacokinetic indices were calculated for each subject by noncompartmental techniques. RESULTS: Thirty-two subjects (6.7 +/- 5.0 years, 11 boys) participated. Mean serum concentration-time data were comparable for the 4 age groups. For all subjects with evaluable data, the mean area under the curve from 0 to 72 hours (AUC0-72) was 8.2 microg . h/mL (n = 26), the maximum concentration (Cmax) was 2.4 microg/mL and the elimination half-life (t1/2) was 65.2 hours (n = 25). The AUC0-72 and Cmax were not associated with age. The dose was well-tolerated with no serious adverse events. CONCLUSION: The disposition of azithromycin after a single 10-mg/kg IV dose (maximum labeled adult dose of 500 mg) is comparable in pediatric patients between 0.5 and 16 years of age. These pharmacokinetic data can be used to guide dose selection for future therapeutic trials of IV azithromycin in pediatric patients.     

Incidence of potentially toxic concentrations of gentamicin in the neonate

The incidence of putatively toxic serum concentrations and the factors influencing their occurrence were investigated in a study of 91 neonates receiving parenteral gentamicin twice daily at a dose of mean (SD) 5.5 (0.1) mg/kg/day. Most neonates were preterm and of low birthweight. Serum concentrations, area under the curve (AUC), and clearance were calculated. Potentially toxic trough concentrations (greater than 2 mg/l) were recorded in 57 of 91 (63%) neonates; 24 of these had trough concentrations greater than 3 mg/l. These babies were of a significantly lower gestational age and were younger than the remainder of the population. Toxic trough concentrations were not accompanied by raised peak serum values. A wide variation in all pharmacokinetic variables was observed. Peak serum concentration was most highly correlated with dose, while trough concentration, AUC, and clearance were more dependent on postnatal age. Clearance of gentamicin decreased significantly with increasing serum urea and creatinine concentrations. Preterm neonates in the first week of life are likely to develop potentially toxic serum concentrations when receiving the currently recommended dose of gentamicin (5-6 mg/kg/day). To prevent accumulation the dosage interval may need to be increased to 18 hours in these babies.     

Incidence of potentially toxic concentrations of gentamicin in the neonate.

The incidence of putatively toxic serum concentrations and the factors influencing their occurrence were investigated in a study of 91 neonates receiving parenteral gentamicin twice daily at a dose of mean (SD) 5.5 (0.1) mg/kg/day. Most neonates were preterm and of low birthweight. Serum concentrations, area under the curve (AUC), and clearance were calculated. Potentially toxic trough concentrations (greater than 2 mg/l) were recorded in 57 of 91 (63%) neonates; 24 of these had trough concentrations greater than 3 mg/l. These babies were of a significantly lower gestational age and were younger than the remainder of the population. Toxic trough concentrations were not accompanied by raised peak serum values. A wide variation in all pharmacokinetic variables was observed. Peak serum concentration was most highly correlated with dose, while trough concentration, AUC, and clearance were more dependent on postnatal age. Clearance of gentamicin decreased significantly with increasing serum urea and creatinine concentrations. Preterm neonates in the first week of life are likely to develop potentially toxic serum concentrations when receiving the currently recommended dose of gentamicin (5-6 mg/kg/day). To prevent accumulation the dosage interval may need to be increased to 18 hours in these babies.