Pharmacokinetics and pharmacodynamics of linezolid in children with cystic fibrosis.

UNLABELLED: Alternative antimicrobial regimens are needed for treatment of methicillin-resistant Staphylococcus aureus (MRSA)-associated pulmonary exacerbations in children with cystic fibrosis (CF). There are no published pharmacokinetic (PK) and pharmacodynamic (PD) data for linezolid in children with CF. OBJECTIVES: (1) To determine the PK and PD profile of linezolid among children with CF; (2) to characterize the effect of linezolid on MRSA infection; (3) to determine the effect of age and CF transmembrane regulator (CFTR) gene mutations on drug clearance. HYPOTHESES: Linezolid clearance is enhanced in children with CF requiring a higher dosage regimen. Age and CFTR gene mutations affect drug clearance. METHODS: This was a retrospective cohort study; medical records of children with MRSA-associated pulmonary exacerbations treated with linezolid (10 mg/kg/dose IV every 8h) were reviewed. Linezolid peak and trough concentrations in serum were determined by high performance liquid chromatography, PK profiles determined using standard noncompartmental method, and PD indices were evaluated. RESULTS: 10 children (mean +/- SD, 10.2 +/- 5.5 years) received 14 courses of linezolid at 10 +/- 0.4 mg/kg/dose every 8h for 15.4 +/- 3.2 days. Seven had homozygous DeltaF508 CFTR mutation. Peak and trough linezolid concentrations varied widely (range, 8.4-20.5 and 0.1-11.5 mcg/mL respectively). The PK profile of children <10 years differed significantly from older patients (>or=10 years). The PK indices of children with homozygous DeltaF508 differed marginally from those with heterozygous CFTR mutations, but there were too few subjects to allow separation of age and CFTR mutations effect. No patient achieved the target PD ratio of AUC/MIC >80. MRSA persisted in sputum or throat culture after treatment with linezolid. CONCLUSIONS: Additional PK and PD data are needed to optimize linezolid therapy in children with cystic fibrosis; it is likely that higher doses will be needed.

Growth hormone treatment improves growth and clinical status in prepubertal children with cystic fibrosis: results of a multicenter randomized controlled trial.

CONTEXT: This multicenter, randomized, controlled, crossover trial of prepubertal children with cystic fibrosis (CF) tests the hypotheses that recombinant human GH (rhGH) treatment 1) improves height, weight, lean mass, and bone content irrespective of baseline measures; 2) improves clinical status and quality of life; and 3) has continued effect after cessation after 1 yr of treatment. METHODS: Sixty-one prepubertal subjects (

Growth hormone improves bone mineral content in children with cystic fibrosis.

AIM: Osteoporosis and osteopenia have been reported as common complications of cystic fibrosis (CF); however, little is known about accrual of bone mineral in CF. The goal of our study was to measure bone mineral content (BMC) in non-acutely-ill, but poorly growing children with CF, and to determine the relationship between height, lean body mass and BMC. Our second aim was to evaluate the effect of one year of treatment with human recombinant growth hormone (GH) on total body BMC. METHODS: We measured total-body BMC using dual energy X-ray absorptiometry in 32 poorly growing (height < or =10th percentile for age) prepubertal Caucasian children (ages 7 years 6 months-12 years 9 months, 17 M and 15, F) with CF. BMC and lean tissue mass (LTM) were measured at baseline, at 6 months and one year. One half of the children were randomly assigned to receive treatment with GH (GHTX). Results were compared to reference data maintained for healthy children matched for age and ethnicity. Sex steroid and IGF-I levels were also measured. RESULTS: Children with CF exhibited lower total body BMC and LTM than age-, ethnicity- and gender-matched controls. This was still apparent when the data were matched for height and bone age. BMC correlated with height, LTM, and IGF-I levels. Although at baseline the groups were similar, the GHTX group demonstrated significantly greater increase in height, weight, LTM and BMC than the NonTX group. These differences remained despite correction for increase in height CONCLUSION: Our study is the first to evaluate BMC in children with CF and suggests that poor accumulation of bone mineral is a problem. We have further demonstrated that GH treatment improves accumulation of bone mineral.

A retrospective study of growth hormone use in adolescents with cystic fibrosis.

OBJECTIVES: Studies of growth hormone (GH) effectiveness in prepubertal children with cystic fibrosis (CF) have been published previously. We present a retrospective study of GH treatment in adolescents with CF. STUDY DESIGN: We performed a retrospective evaluation of data from 25 pubertal adolescents (ages 13 years 4 months to 16 years 11 months, Tanner stage III or IV). Thirteen (4 F) were followed for 1 year, then received 1 year of treatment with GH (GHTX). We compared the results with a 'control' group of 12 (4 F) whose growth was followed for 1 year (NonTX) but who were not treated with GH at the time of this review. Anthropometric data included: height, weight, lean tissue mass (LTM) and bone mineral content (BMC). Pulmonary function, number of hospitalizations, glycosylated haemoglobin (HbA1c), random blood glucose levels, IGF-I, oestradiol and testosterone levels are also reported. RESULTS: There was no difference between the groups at baseline. After 1 year, GHTX had significantly greater height and weight velocity, height and weight Z-scores, body mass index (BMI), LTM and BMC. Absolute pulmonary function was better and hospitalizations were fewer in the GHTX. No subject developed glucose intolerance or had any other side-effects. CONCLUSION: These results suggest that GH use in pubertal adolescents with CF safely improves height, body weight, bone mineralization and clinical status.

Growth hormone treatment enhances nutrition and growth in children with cystic fibrosis receiving enteral nutrition.

OBJECTIVES: Impaired longitudinal growth and poor weight gain are common and important problems in children with cystic fibrosis. This study evaluates the hypothesis that adjunctive growth hormone (GH) therapy augments the growth response to nutritional supplementation. STUDY DESIGN: We recruited 18 prepubertal children who received enteral nutritional supplementation for at least 2 years before enrollment. Nine were randomly assigned to receive no GH for 1 year, followed by 1 year of GH. Nine were randomly assigned to receive 1 year of GH followed by a second year of GH. Measurements included height, weight, pulmonary function, lean tissue mass, bone mineral content, hospitalizations, outpatient antibiotic use, and caloric intake. RESULTS: Growth hormone resulted in significant improvement in height, weight, bone mineral content, lean tissue mass, and number of hospitalizations. Pulmonary function was similar at baseline. Absolute forced vital capacity and forced expiratory volume in 1 minute significantly increased in GH treatment, but there was no significant change in percent predicted pulmonary function. Caloric intake was similar in both groups during both years. CONCLUSIONS: These results suggest that GH is a useful for enhancing growth in children with cystic fibrosis receiving enteral nutritional supplementation.

Liver transplantation for cholestasis associated with cystic fibrosis in the pediatric population.

The most common hepatic complications of cystic fibrosis (CF) are steatosis, fibrosis, biliary cirrhosis, atretic gallbladder, cholelithiasis, and sclerosing cholangitis. Cholestatic liver disease is a slow progressive disorder, but will stabilize for many patients. CF patients may suffer from the consequences of their liver disease and without liver transplantation, variceal hemorrhage, malnutrition, or end-stage liver disease can lead to death. Prospective data were collected and reviewed on 311 liver transplants performed in 283 patients at the Children's Medical Center of Dallas between October 1984 and November 2000. Ten children received an orthotopic liver transplant (OTLX) for end-stage liver disease associated with cystic fibrosis. Pulmonary function tests were obtained preoperatively in all cases. There were nine boys and one girl. Six are currently alive, and four are dead. Both patient and graft survival was 5.75 yr. Among those currently alive, mean patient and graft survival is 7.71 yr (range 0.10-12.62 yr). Mean patient and graft survival of those who died was 2.35 yr (range 0.78-5.33 yr). No survivor required re-transplantation and currently, all have normal serum aminotransferase values. Chronic sinusitis was not a significant pre- or post-transplant morbidity, although systematic radiographic evaluation of the sinuses did not occur. Pulmonary deaths occurred in three patients from pulmonary hemorrhage, pulmonary infection with Aspergillus and Candida glabrata, and acute bronchopneumonia associated with polymicrobial sepsis because of Pseudomonas, Klebsiella, and Candida albicans 1.44, 0.78, and 1.83 yr, respectively, after transplantation. The fourth death was associated with chronic rejection, and occurred 5.33 yr after transplantation. All non-survivors were below the 5th percentile for height and weight at the time of liver transplantation. Mean age at transplantation was 9.72 yr (range 1.23-19.09, median 9.61). Survivors were transplanted at a younger age than non-survivors (mean of 9.21 yr vs. 10.66 yr), and had shorter waiting times from diagnosis of end-stage liver disease to transplantation (6.87 months vs. 13.83 months). Eighty percentage (n = 8) of patients had pretransplant variceal bleeds (83% of survivors, 75% of non-survivors). While all non-survivors had a history of meconium ileus and preoperative need of pancreatic enzymes, only 67% of those alive experienced these complications. Preoperative forced vital capacity FVC was 103% for survivors and 95% for non-survivors. The corresponding numbers for forced expiratory flow (FEF) 25-75 were 74-84% respectively. Preoperative Aspergillus was identified in 30% of patients (n = 3). Two of these patients are alive. Cystic fibrosis constitutes an indication for 3.5% of pediatric liver transplants. Evaluation and transplantation for end-stage liver disease associated with cystic fibrosis should be undertaken at an early age. Most deaths were associated with pulmonary/septic events, and occurred less than 2 yr after OLTX. Those children who did not survive had poor growth and nutrition, prolonged waiting times prior to transplantation, were transplanted at an older age, and had a higher incidence of pancreatic insufficiency and meconium ileus. The presence of Aspergillus in the sputum does not constitute a contraindication for OLTX.