What are the most appropriate antibiotics for the treatment of acute exacerbation of chronic obstructive pulmonary disease? A therapeutic outcomes model

OBJECTIVES: To predict the clinical efficacy of several antimicrobials in the treatment of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: A probability model (therapeutic outcomes model) was used to predict the likelihood of clinical success with particular antimicrobial agents in the treatment of patients with AECOPD, both in those clinically diagnosed (total patients with an AECOPD diagnosis regardless of the cause) and in those with bacterial AECOPD. The model took into account the following variables: (i) the proportion of patients with a clinical diagnosis of AECOPD and non-bacterial disease; (ii) likelihood of spontaneous resolution of a non-bacterial infection; (iii) prevalence of subcauses (different bacterial species) in bacterial AECOPD; (iv) rates of spontaneous resolution of bacterial AECOPD; and (v) antimicrobial efficacy of each antibiotic against each bacterial species (susceptibility based on PK/PD breakpoints). RESULTS: Fluoroquinolones (levofloxacin, ciprofloxacin and moxifloxacin), a new third-generation oral cephalosporin (cefditoren) and high doses of amoxicillin/clavulanate were the antimicrobials with the highest predicted clinical efficacy both in mild-moderate AECOPD and in severe AECOPD (rates of 89.2% to 90.5% and 80.3% to 88.1%, respectively), whereas cefaclor, azithromycin, erythromycin and clarithromycin had the lowest predicted clinical efficacy (rates of 79.1% to 81.3% and 51.8% to 55.6% for mild-moderate and severe AECOPD, respectively), which was not much higher than that predicted for placebo (73.6% and 45.5%, respectively). CONCLUSIONS: According to our model, fluoroquinolones (levofloxacin, ciprofloxacin and moxifloxacin), cefditoren and amoxicillin/clavulanate are the most appropriate antibiotics for the treatment of patients with AECOPD in terms of predicted clinical efficacy, with wide differences with respect to other antibiotics commonly used in the treatment of these patients, such as clarithromycin and azithromycin.     

CDKL5 gene status in female patients with epilepsy and Rett-like features: two new mutations in the catalytic domain

ABSTRACT: BACKGROUND: Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) located in the Xp22 region have been shown to cause a subset of atypical Rett syndrome with infantile spasms or early seizures starting in the first postnatal months. METHODS: We performed mutation screening of CDKL5 in 60 female patients who had been identified as negative for the methyl CpG-binding protein 2 gene (MECP2) mutations, but who had current or past epilepsy, regardless of the age of onset, type, and severity. All the exons in the CDKL5 gene and their neighbouring sequences were examined, and CDKL5 rearrangements were studied by multiplex ligation-dependent probe amplification (MLPA). RESULTS: Six previously unidentified DNA changes were detected, two of which were disease-causing mutations in the catalytic domain: a frameshift mutation (c.509_510insGT; p.Glu170GlyfsX36) and a complete deletion of exon 10. Both were found in patients with seizures that started in the first month of life. CONCLUSIONS: This study demonstrated the importance of CDKL5 mutations as etiological factors in neurodevelopmental disorders, and indicated that a thorough analysis of the CDKL5 gene sequence and its rearrangements should be considered in females with Rett syndrome-like phenotypes, severe encephalopathy and epilepsy with onset before 5 months of age. This study also confirmed the usefulness of MLPA as a diagnostic screening method for use in clinical practice.     

Molecular characterization of Spanish patients with MECP2 duplication syndrome

MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder characterized by a severe to profound intellectual disability, early onset hypotonia and diverse psycho-motor and behavioural features. To date, fewer than 200 cases have been published. We report the clinical and molecular characterization of a Spanish MDS cohort that included 19 boys and 2 girls. Clinical suspicions were confirmed by array comparative genomic hybridization and multiplex ligation-dependent probe amplification (MLPA). Using, a custom in-house MLPA assay, we performed a thorough study of the minimal duplicated region, from which we concluded a complete duplication of both MECP2 and IRAK1 was necessary for a correct MDS diagnosis, as patients with partial MECP2 duplications lacked some typical clinical traits present in other MDS patients. In addition, the duplication location may be related to phenotypic severity. This observation may provide a new approach for genotype-phenotype correlations, and thus more personalized genetic counselling.