Use of linezolid in neonatal and pediatric inpatient facilities-results of a retrospective multicenter survey

The purpose of this investigation was to describe the use of linezolid in pediatric inpatient facilities. A retrospective multicenter survey including data from nine participating tertiary care pediatric inpatient facilities in Germany and Austria was undertaken. Data on 126 off-label linezolid treatment courses administered to 108 patients were documented. The survey comprises linezolid treatment in a broad spectrum of clinical indications to children of all age groups; the median age was 6.8 years (interquartile range 0.6-15.5 years; range 0.1-21.2 years; ten patients were older than 18 years of age but were treated in pediatric inpatient units). Of the 126 treatment courses, 27 (21%) were administered to preterm infants, 64 (51%) to pediatric oncology patients, and 5% to patients soon after liver transplantation. In 25%, the infection was related to a medical device. Linezolid iv treatment was started after intensive pre-treatment (up to 11 other antibiotics for a median duration of 14 days) and changed to enteral administration in only 4% of all iv courses. In 39 (53%) of 74 courses administered to children older than 1 week and younger than 12 years of age, the dose was not adjusted to age-related pharmacokinetic parameters. In only 17 courses (13%) was a pediatric infectious disease consultant involved in the clinical decision algorithm. Linezolid seemed to have contributed to a favorable outcome in 70% of all treatment courses in this survey. Although retrospective, this survey generates interesting data on the off-label use of linezolid and highlights several important clinical aspects in which the use of this rescue antibiotic in children might be improved

Mitochondrial Transporter Defects: Successful Treatment with Ketogenic Diet Therapy

Background/Purpose: No causal treatment for mitochondrial disease exists. Exome sequencing allows to identify specific mitochondrial defects (theoretically) amenable to dietary intervention. The mitochondrial transporters aspartate glutamate carrier 1 (AGC1) and mitochondrial pyruvate carrier 1 (MPC1) are tightly linked to glucose catabolism. Successful pathomechanism-based treatment of such defects with ketogenic diet (KD) was reported in two patients with AGC1-deficiency and a MPC1-deficient mouse model. Methods: The Munich exome database was queried for AGC1- and MPC1-deficient patients. Clinical and neuroradiological details were collected and literature cases reviewed. Results: Six MPC1-deficient individuals (4 reported, 2 novel) were identified and outcome on KD reported in 2 (1 novel). The phenotype beside developmental impairment (6/6) and elevated serum lactate (6/6) was variable with epilepsy (3/6), microcephaly (3/6), and the first report of one patient with splenomegaly, diabetes mellitus and bone fractures. In contrast to the previously reported infant, our severely affected patient improved distinctly on KD, with seizure freedom and developmental progress. Thirteen AGC1-deficient individuals (8 reported, 5 novel) were identified. Seven of 13 received KD. All had infantile-onset epilepsy, severe developmental impairment and muscular hypotonia. MRI revealed brain atrophy (9/9) and reduced myelination (7/9), MRS showed reduced n-acetyl-aspartate (5/6). Elevated serum lactate was found in 8 of 13. In six of seven patients, KD showed impressive improvement on seizure frequency, development, and neuroradiological features. Conclusion: Treatment with KD is beneficial in patients with AGC1 and MPC1 deficiency. This underlines the importance for early genetic diagnostics in patients with epilepsy especially with additional markers raising suspicion of mitochondrial disease

Ketogenic Diet Treatment of Defects in the Mitochondrial Malate Aspartate Shuttle and Pyruvate Carrier

The mitochondrial malate aspartate shuttle system (MAS) maintains the cytosolic NAD+/NADH redox balance, thereby sustaining cytosolic redox-dependent pathways, such as glycolysis and serine biosynthesis. Human disease has been associated with defects in four MAS-proteins (encoded by MDH1, MDH2, GOT2, SLC25A12) sharing a neurological/epileptic phenotype, as well as citrin deficiency (SLC25A13) with a complex hepatopathic-neuropsychiatric phenotype. Ketogenic diets (KD) are high-fat/low-carbohydrate diets, which decrease glycolysis thus bypassing the mentioned defects. The same holds for mitochondrial pyruvate carrier (MPC) 1 deficiency, which also presents neurological deficits. We here describe 40 (18 previously unreported) subjects with MAS-/MPC1-defects (32 neurological phenotypes, eight citrin deficiency), describe and discuss their phenotypes and genotypes (presenting 12 novel variants), and the efficacy of KD. Of 13 MAS/MPC1-individuals with a neurological phenotype treated with KD, 11 experienced benefits-mainly a striking effect against seizures. Two individuals with citrin deficiency deceased before the correct diagnosis was established, presumably due to high-carbohydrate treatment. Six citrin-deficient individuals received a carbohydrate-restricted/fat-enriched diet and showed normalisation of laboratory values/hepatopathy as well as age-adequate thriving. We conclude that patients with MAS-/MPC1-defects are amenable to dietary intervention and that early (genetic) diagnosis is key for initiation of proper treatment and can even be lifesaving