Jean-Christophe Dubus

Colistin: an update on the antibiotic of the 21st century

The emergence of multidrug-resistant Gram-negative bacteria that cause nosocomial infections is a growing problem worldwide. Colistin was first introduced in 1952 and was used until the early 1980s for the treatment of infections caused by Gram-negative bacilli. In vitro, colistin has demonstrated excellent activity against various Gram-negative rod-shaped bacteria, including multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Recent clinical findings regarding colistin activity, pharmacokinetic properties, clinical uses, emerging resistance, toxicities and combination therapy have been reviewed. Recent approaches to the use of colistin in combination with other antibiotics hold promise for increased antibacterial efficacy. It is probable that colistin will be the ‘last-line’ therapeutic drug against multidrug-resistant Gram-negative pathogens in the 21st century.

Molecular Detection of Multiple Emerging Pathogens in Sputa from Cystic Fibrosis Patients

Background There is strong evidence that culture-based methods detect only a small proportion of bacteria present in the respiratory tracts of cystic fibrosis (CF) patients. Methodology/Principal Findings Standard microbiological culture and phenotypic identification of bacteria in sputa from CF patients have been compared to molecular methods by the use of 16S rDNA amplification, cloning and sequencing. Twenty-five sputa from CF patients were cultured that yield 33 isolates (13 species) known to be pathogens during CF. For molecular cloning, 760 clones were sequenced (7.2±3.9 species/sputum), and 53 different bacterial species were identified including 16 species of anaerobes (30%). Discrepancies between culture and molecular data were numerous and demonstrate that accurate identification remains challenging. New or emerging bacteria not or rarely reported in CF patients were detected including Dolosigranulum pigrum, Dialister pneumosintes, and Inquilinus limosus. Conclusions/Significance Our results demonstrate the complex microbial community in sputa from CF patients, especially anaerobic bacteria that are probably an underestimated cause of CF lung pathology. Metagenomic analysis is urgently needed to better understand those complex communities in CF pulmonary infections.

Microbial diversity in the sputum of a cystic fibrosis patient studied with 16S rDNA pyrosequencing

Recent studies using 16S rRNA gene amplification followed by clonal Sanger sequencing in cystic fibrosis demonstrated that cultured microorganisms are only part of the infecting flora. The purpose of this paper was to compare pyrosequencing and clonal Sanger sequencing on sputum. The sputum of a patient with cystic fibrosis was analysed by culture, Sanger clone sequencing and pyrosequencing after 16S rRNA gene amplification. A total of 4,499 sequencing reads were obtained, which could be attributed to six consensus sequences, but the length of reads leads to fastidious data analysis. Compared to clonal Sanger sequencing and to cultivation results, pyrosequencing recovers greater species richness and gives a more reliable estimate of the relative abundance of bacterial species. The 16S pyrosequencing approach expands our knowledge of the microbial diversity of cystic fibrosis sputum. The current lack of phylogenetic resolution at the species level for the GS 20 sequencing reads will be overcome with the next generation of pyrosequencing apparatus.

Add-on omalizumab in children with severe allergic asthma: a 1-year real life survey

Omalizumab has been shown to reduce exacerbation rates in moderate to severe allergic asthma. Our aim was to evaluate omalizumab efficacy and safety in a real-life setting in severe asthmatic children. 104 children (aged 6–18 years), followed up in paediatric pulmonary tertiary care centres, were included at the beginning of omalizumab treatment. Asthma control levels, exacerbations, inhaled corticosteroid dose, lung function and adverse events were evaluated over 1 year. Children were characterised by allergic sensitisation to three or more allergens (66%), high IgE levels (mean 1125 kU·L−1), high rate of exacerbations (4.4 per year) and healthcare use during the previous year, and high inhaled corticosteroid dose (mean 703 &mgr;g equivalent fluticasone per day). Asthma control levels defined as good, partial or poor, improved from 0%, 18% and 82% at entry to 53%, 30% and 17% at week 20, and to 67%, 25% and 8% at week 52, respectively (p<0.0001). Exacerbation and hospitalisation rates dropped by 72% and 88.5%, respectively. At 12 months, forced expiratory volume in 1 s improved by 4.9% (p=0.023), and inhaled corticosteroid dose decreased by 30% (p<0.001). Six patients stopped omalizumab for related significant adverse events. Omalizumab improved asthma control in children with severe allergic asthma and was generally well tolerated. The observed benefit was greater than that reported in clinical trials. Omalizumab improves asthma control in children with severe allergic asthma and is generally well tolerated http://ow.ly/oLoBp

Risk factors for Aspergillus colonization and allergic bronchopulmonary aspergillosis in children with cystic fibrosis.

The annual prevalence of Aspergillus colonization (AC) and allergic bronchopulmonary aspergillosis (ABPA) has recently increased in pediatric patients with cystic fibrosis (CF). The reasons remain unclear although a number of factors have been suggested to be involved. This study was set up to investigate the association between potential predisposing factors, including new therapies recommended in CF, and the occurrence of AC or ABPA in children with CF.

Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children

ABCA3 (ATP-binding cassette subfamily A, member 3) is expressed in the lamellar bodies of alveolar type II cells and is crucial to pulmonary surfactant storage and homeostasis. ABCA3 gene mutations have been associated with neonatal respiratory distress (NRD) and pediatric interstitial lung disease (ILD). The objective of this study was to look for ABCA3 gene mutations in patients with severe NRD and/or ILD. The 30 ABCA3 coding exons were screened in 47 patients with severe NRD and/or ILD. ABCA3 mutations were identified in 10 out of 47 patients, including 2 homozygous, 5 compound heterozygous and 3 heterozygous patients. SP-B and SP-C expression patterns varied across patients. Among patients with ABCA3 mutations, five died shortly after birth and five developed ILD (including one without NRD). Functional studies of p.D253H and p.T1173R mutations revealed that p.D253H and p.T1173R induced abnormal lamellar bodies. Additionally, p.T1173R increased IL-8 secretion in vitro. In conclusion, we identified new ABCA3 mutations in patients with life-threatening NRD and/or ILD. Two mutations associated with ILD acted via different pathophysiological mechanisms despite similar clinical phenotypes.

First isolation of two colistin-resistant emerging pathogens, Brevundimonas diminuta and Ochrobactrum anthropi, in a woman with cystic fibrosis: a case report

IntroductionCystic fibrosis afflicted lungs support the growth of many bacteria rarely implicated in other cases of human infections.Case presentationWe report the isolation and identification, by 16S rRNA amplification and sequencing, of two emerging pathogens resistant to colistin, Brevundimonas diminuta and Ochrobactrum anthropi, in a 17-year-old woman with cystic fibrosis and pneumonia. The patient eventually responded well to a 2-week regime of imipenem and tobramycin.ConclusionOur results clearly re-emphasize the emergence of new colistin-resistant pathogens in patients with cystic fibrosis.

Real-life long-term omalizumab therapy in children with severe allergic asthma

We previously reported the French real-life experience of 1 year of add-on treatment with omalizumab in 101 severe allergic asthmatic children (6–18 years), 92 of whom were still receiving the treatment at the end of the first year [1]. The study provided complementary data to the previous randomised trials [2–6]. We showed a marked drop of 72% in the mean rate of severe exacerbations (from 4.4 per patient during the preceding year to 1.25 during the year of treatment) and of 88.5% for hospitalisations (44% of the patients during the preceding year to 6.7% during the year of treatment); a large improvement in asthma control (from 0% at initiation to 67% of well-controlled patients after 1 year); a decrease of 30% of the mean inhaled corticosteroid (ICS) dose (from 703 at initiation to 488 µg fluticasone equivalent per day after 1 year); and a forced expiratory volume in 1 s (FEV1) increase, from a mean of 88% to 92.1% of the predicted value. Treatment was discontinued in six patients due to serious adverse events attributed to omalizumab by the practitioner. Here we report the outcome of this cohort after 2 years of omalizumab treatment. Beneficial effects at 2 years of omalizumab on severe exacerbations and control in severe allergic asthmatic children http://ow.ly/LGgnw

Disposable versus reusable jet nebulizers for cystic fibrosis treatment with tobramycin.

BACKGROUND Jet nebulizers are commonly used to administer aerosolized tobramycin to CF patients. The aim of this study was to assess the performance of disposable jet nebulizers as an alternative to reusable nebulizers such as the Pari LC Plus. METHOD From a survey conducted in 49 CF centers in France, 18 disposable jet nebulizer systems were selected. An in vitro study was performed with 20 jet nebulizer/air source combinations (18 disposable and 2 reusable) to determine their performance with tobramycin solution (300 mg/5 mL). A scintigraphic deposition study in baboons was performed to validate the in vitro data. RESULTS In vitro and in vivo results correlated. There was no overall relationship between the compressed air source and nebulizer performance, but the nebulizer interface was responsible for significantly different results. CONCLUSIONS None of the disposable nebulizers tested in this study can be recommended as an alternative to the Pari LC Plus nebulizer for tobramycin.

Hospitalizations for Asthma in Children Are Linked to Undertreatment and Insufficient Asthma Education

Background. Most hospital admissions for asthma exacerbation are avoidable with adequate disease management. Objectives. The objective of this study was to describe the characteristics of children hospitalized with an asthma exacerbation to identify modifiable factors leading to hospitalization. Methods. The study was conducted in 14 pediatric units and included children 3–17 years of age who were hospitalized for an asthma exacerbation. The present analysis covers 498 children with known asthma. Staff physicians used a standardized questionnaire to collect data. Asthma history came from a parental interview and included usual asthma care, frequency of symptoms and quick-relief medication use in the previous month, frequency of exacerbations and number of unscheduled healthcare visits during the past year, and prior asthma-related hospitalizations. Results. More than half the children had previously been hospitalized for an exacerbation, 42% used continuous inhaled corticosteroids, and 57% had a regular follow-up for asthma. Asthma had been well controlled over the past year for 11%, 12% had experienced exacerbations during the past year but that had been optimally controlled during the previous month, and 11% had recently become poorly controlled (infrequent exacerbations in the previous year and non-optimal control in the previous month). The remaining 327 children (66%) were consistently poorly controlled (non-optimal asthma control in the previous month and frequent exacerbations over the previous year). Among this group, 69% had at least one of the following preventable risk factors for hospitalization: no regular controller therapy (49%), no asthma action plan (40%), or no follow-up for asthma (35%). Conclusions. Two-thirds of the children with asthma hospitalized for an exacerbation had been consistently poorly controlled during the previous year. They were frequently undertreated and insufficiently educated about asthma. Further efforts are needed to improve asthma treatment and education in France.