Population pharmacokinetics of ceftazidime in critically ill children: impact of cystic fibrosis.

BACKGROUND: Pharmacokinetics data on ceftazidime are sparse for the paediatric population, particularly for children with cystic fibrosis (CF) or severe infections. OBJECTIVES: To characterize the population pharmacokinetics of ceftazidime in critically ill children, identify covariates that affect drug disposition and evaluate the current dosing regimens. METHODS: The study was registered with Clinicaltrials.gov (NCT01344512). Children receiving ceftazidime were selected in 13 French hospitals. Plasma concentrations were determined by UPLC-MS/MS. Population pharmacokinetic analyses were performed using NONMEN software. RESULTS: One hundred and eight patients, aged 28 days to 12 years, with CF (n = 32), haematology and/or oncology disorders (n = 47) or severe infection (n = 29) were included. Ceftazidime was administered by continuous or intermittent infusions; 271 samples were available for analysis. A two-compartment model with first-order elimination and allometric scaling was developed and covariate analysis showed that ceftazidime pharmacokinetics were also significantly affected by CLCR and CF. Ceftazidime clearance was 82% higher in CF than in non-CF patients. Monte Carlo simulations showed that the percentage of target attainment (PTA) for the target of T>MIC = 65% was (i) lower in CF than in non-CF children with intermittent infusions and (ii) higher with continuous than intermittent infusion in all children. CONCLUSIONS: The population pharmacokinetics model for ceftazidime in children was influenced by body weight, CLCR and CF. A higher PTA was obtained with continuous versus intermittent infusions. Further studies should explore the benefits of continuous versus intermittent infusion of ceftazidime, including current versus increased doses in CF children.

Variability of ciprofloxacin pharmacokinetics in children: impact on dose range in sickle cell patients.

Objectives: To determine the ciprofloxacin population pharmacokinetics in paediatric patients and the impact of underlying disease and evaluate the appropriateness of current dosage regimens. Patients and methods: Plasma concentrations of ciprofloxacin from children treated with ciprofloxacin were measured by HPLC. The pharmacokinetic population analysis was performed using NONMEM v7.2 (Icon Development Solutions, USA). Results: Two datasets were combined and 128 plasma concentrations in 60 patients aged 5.6 years (range 0.3-18.9), treated with a median daily dose of 30.0 mg/kg (range 6.5-52.0) presenting with sickle cell disease (SCD; n = 20, 33%), haemopathy (n = 15, 25%), cystic fibrosis (CF; n = 3, 5%) and other diseases (n  =  22, 37%) were analysed. Data were best described by a two-compartment model with first-order elimination. Ciprofloxacin clearance (mean ±â€Šâ€ŠSD) was 0.81 ±â€Š0.30 L/h/kg, increased allometrically with weight, decreased with increasing creatinine concentration, was 89% higher in SCD compared with non-SCD patients and increased by 0.95 L/h/kg per year of age. The volume of distribution was 6.9 L/kg and depended only on the weight. Monte Carlo simulations were performed separately in SCD and non-SCD patients to target an AUC/MIC ratio >125 at steady-state, required for antibacterial efficacy, and recommendations of dosing regimens were proposed. Conclusions: In addition to known covariates, ciprofloxacin clearance is greater in SCD children compared with non-SCD patients. The dosing of this agent needs to be adapted to this subgroup of patients.

Remodelling and inflammation in preschoolers with severe recurrent wheeze and asthma outcome at school age.

BACKGROUND: The influence of airway remodelling and inflammation in preschoolers with severe recurrent wheeze on asthma outcomes is poorly understood. OBJECTIVE: To assess their association with asthma symptoms and lung function at school age. METHODS: Preschoolers (38.4 months) initially investigated with bronchial biopsies were re-assessed for asthma symptoms and lung function at school age. RESULTS: Thirty-six of 49 preschoolers (73.5%) were assessed at 10.9 years. Twenty-six (72.2%) had persistent asthma. Submucosal eosinophil counts were higher in children with severe exacerbations at school age than in those without (16/0.1 mm2 [11.2-30.4] vs 8/0.1 mm2 [2.4-17.6], P = .02), and correlated with the number of severe exacerbations (P = .04, r = .35). Submucosal neutrophil counts correlated with FEV1/FVC (P < .01, r = .47) and FEF25-75% predicted (P = .02, r = .43). Airway smooth muscle (ASM) area correlated with FEV1/FVC (P < .01, r = .51). Vessel numbers negatively correlated with FEV1% predicted and FEV1/FVC (P = .03, r = -.42; P = .04, r = -.41; respectively) and FEF25-75% predicted (P = .02, r = -.46). CONCLUSION: Eosinophilic inflammation in preschoolers with severe recurrent wheeze might be predictive of future severe exacerbations, neutrophilia might be associated with better lung function. Changes in ASM and vascularity might affect lung function at school age.

Exploring the expression of Pseudomonas aeruginosa genes directly from sputa of cystic fibrosis patients.

UNLABELLED: Acquisition of Pseudomonas aeruginosa is known as a negative prognostic factor in patients with cystic fibrosis. We started a pilot study to evaluate Ps. aeruginosa gene expression directly from the sputum of infected patients. Total RNA was purified from 15 sputum samples collected from 10 patients, and the expression levels of five genes from Ps. aeruginosa were measured by RT-qPCR. Expression of algD, algR, antB, lasB and pqsA genes was determined in sputa that contained Ps. aeruginosa cells. The resultant data provided an overview of the expression of these genes in CF patients. Except for the correlation between algD expression and the mucoid phenotype, the gene expression profile could not be associated with the clinical status of patients. However, beyond the heterogeneity of the Ps. aeruginosa phenotype in sputum, we observed a correlation between the expression of antB and pqsA and a low level of lasB transcripts. SIGNIFICANCE AND IMPACT OF THE STUDY: Pseudomonas aeruginosa infection leads to high morbidity and mortality in cystic fibrosis patients. The identification of Ps. aeruginosa-assigned factors is important to eradicate the colonization. We started a pilot study to evaluate the gene expression of Ps. aeruginosa directly from the sputum of infected patients. Preliminary results suggest that beyond the heterogeneity of the Ps. aeruginosa phenotype in sputum, we observe a correlation between the expression of antB and pqsA and a low level of lasB transcripts. This approach could shed some light on the behaviour of Ps. aeruginosa during pulmonary infection and may reveal some important elements for optimizing therapy.

RECURRENCE OF POMPE DISEASE IN FIRST COUSINS.

We report on the cases of two first-degree non-consanguineous cousins with infantile-onset Pompe disease, a rare autosomal recessive disease. The first patient developed cardiorespiratory failure at age 1 year. When she was 4 her male cousin developed hypotonia during his first month of life. Both infants had cardiac hypertrophy at diagnosis and shared the c.1927G>A missense mutation. Since a first degree cousin of an affected patient has 50 times the risk of developing the disease compared with unrelated infants and since cardiac hypertrophy is constant in affected infants, the combination of cardiac symptoms with a history of Pompe disease in a first degree cousin leads to a very high probability of having the condition. Clinically oriented screening based on simple diagnostic procedures such as echocardiogram and anamnesis could accelerate the initiation of enzyme replacement therapy of the deficient acid α-glucosidase which is critical to restoring cardiac function in affected infants.

[Allergic Broncho-Pulmonary Aspergillosis (ABPA) in cystic fibrosis: Mechanisms, diagnosis and therapeutic options]. / Aspergillose bronchopulmonaire allergique (ABPA) et mucoviscidose : mécanismes, diagnostic et alternatives thérapeutiques.

INTRODUCTION: Fungal aspergillosis colonization and allergic bronchopulmonary aspergillosis (ABPA) can have a strong impact on the prognosis in cystic fibrosis (CF). We conducted round table discussions involving French experts from pediatric and adult centers caring for patients with CF, microbiologists, radiologists and pharmacists. The aim was to explore the current state of knowledge on: the pathophysiological mechanisms of Aspergillus and other micromycetes infections in CF (such as Scedosporium sp.), and on the clinico-biological diagnosis of ABPA. In perspective, the experts explored the role of imaging in the diagnosis of APBA, specifically CT and MRI; as well as the role of bronchoscopy in the management. We also reviewed the therapeutic management, including different corticosteroid regimens, antifungals and anti-IgE antibodies. CONCLUSION: The diagnosis of ABPA in CF should be based on more standardized biological assays and imaging to optimize treatment and follow-up.

Epicutaneous aeroallergen sensitization in atopic dermatitis infants - determining the role of epidermal barrier impairment.

BACKGROUND: Sensitization to atopens is an early phenomenon that overlaps with the onset of atopic dermatitis (AD) in infancy. Early epidermal barrier impairment may facilitate the epicutaneous penetration of atopens. OBJECTIVE: To correlate transepidermal water loss (TEWL) and aeroallergen sensitization in infants with AD. METHODS: In this cross-sectional study we enrolled 59 AD children and 30 controls aged 3-12 months. Transepidermal water loss in uninvolved skin, specific immunoglobulin E, atopy patch test (APT) and skin prick tests were performed with respect to seven aeroallergens, i.e., Dermatophagoides pteronyssinus, D. farinae, cat, dog, birch pollen, ambrosia, and cockroach. Environmental conditions were assessed by a questionnaire, and the house dust mite (HDM) concentration was determined in dust samples. RESULTS: Eighty-nine percent of AD infants had a positive APT vs one out of eleven controls. AD infants had a significantly higher mean TEWL than controls (27.4 vs 11.1 g/m(2)/h, P < 0001). Children with two or more positive APT had higher TEWL than the others (31.1 vs 19.0 g/m(2)/h, P < 0.025). No correlation was found between indoor APT results and exposure to HDM, cats, and dogs at home. CONCLUSIONS: This study confirms the high prevalence of delayed sensitization to indoor and outdoor aeroallergens in AD infants, and shows that the higher the TEWL, the higher the prevalence of sensitization to aeroallergens. These data are in favor of a major role of a constitutive epidermal barrier impairment in determining early atopen sensitization in infants with AD.

Low influenza vaccination coverage in asthmatic children in France in 2006-7.

In France, annual seasonal influenza vaccination has been recommended since 2000 for patients suffering from chronic respiratory diseases, including asthma. Since 1988, each year from September to December, a free influenza vaccination voucher is sent by the French Public Health Insurance authorities to patients with chronic respiratory disease, including severe asthma. In November 2006, this measure was extended to all asthmatic patients, irrespective of asthma severity. The present paper examines the 2006-7 influenza vaccination coverage rate (VCR) in 433 asthmatic children aged 6 to 17 years (mean age: 9.5 years; male: 61%) who consulted a paediatric pulmonologist between March and September 2007 in eight hospitals throughout France. The influenza VCR was 15.7% for the 2006-7 season (13.9% for the 2005-6 season and 10.9% for the 2004-5 season). General practitioners vaccinated 72.1% of the children. "Lack of information" (42%) was the most frequently reported reason for non-vaccination. Vouchers (received by 39.6% of the children) significantly increased the VCR (31% versus 5.9%; p<0.001). In France, in 2006-7, the influenza VCR in asthmatic children was far below the national public health objective (at least 75% for the year 2008). Concerted action is needed to improve the influenza VCR in asthmatic children.

[Influenza vaccination coverage in asthmatic children in France in 2006-2007]. / Couverture vaccinale contre la grippe chez les enfants asthmatiques en France en 2006-2007.

In France, an annual seasonal influenza vaccination has been recommended since 2000 for patients suffering from chronic respiratory diseases, including asthma. Each year, a free influenza vaccination voucher is sent by the French Public Health Insurance authorities to patients with chronic respiratory disease, including severe asthma. In November 2006, this measure was extended to all asthmatic patients, irrespective of asthma severity. The present paper examines the 2006-2007 influenza vaccination coverage rate in 433 asthmatic children aged six to 17 years (mean age: 9.5 years; male: 61%) who consulted a pediatric pulmonologist between March and September 2007 in eight hospitals throughout France. The influenza vaccination coverage rate was 15.7% for the 2006-2007 season (13.9% for the 2005-2006 season and 10.9% for the 2004-2005 season). General practitioners vaccinated 72.1% of the children. Lack of information (42%) was the most frequently reported reason for non-vaccination. Free vouchers (received by 39.6% of the children) significantly increased the vaccination coverage rate (31% versus 5.9%; p < 0.001). In France, in 2006-2007, the influenza vaccination coverage rate in asthmatic children was far below the national public health objective to achieve for the year 2008 (at least 75%). Concerted action is needed to improve the influenza vaccination coverage rate in asthmatic children.

[Measurement of pulmonary inflammation in cystic fibrosis]. / Mesure de l'inflammation pulmonaire dans la mucoviscidose.

Lung inflammation is a pivotal phenomenon in the pathogenesis of cystic fibrosis. Inflammation can be measured and quantified within a research perspective, as well as in daily clinical practice. In this review paper, the "Inflammation Task Force" of the "Société Française de Mucoviscidose" has reviewed the literature regarding the various techniques currently available (bronchoalveolar lavage, sputum analysis, nasal wash and brushing, exhaled breath condensates, carbon monoxide and nitric oxide, and systemic measurements (plasma and urine)). The interpretation of all these determinations in children and adults is also discussed.

[Atopic dermatitis aggravates the allergic airways inflammation in acute viral bronchiolitis]. / La dermatite atopique aggrave l'inflammation allergique dans la bronchiolite aiguë virale.

INTRODUCTION: Exhaled nitric oxide (FeNO) is a putative non-invasive marker of eosinophilic airway inflammation with a good predictive value for allergic asthma in preschool children. The aim of the present study was to compare FeNO after acute viral bronchiolitis (AVB) in children aged less than 2 years without atopic dermatitis (AD) vs those with atopic dermatitis, as well as children with AD without any history of AVB. METHODS: Forty-two children (mean age +/- SD: 12.3 +/- 5.2 months; range 5.0-23.5; sex-ratio M: F=1.3: 1) were included in this prospective study, > 8 wks after an episode of AVB. The patients' atopic status was assessed both by clinical phenotype and IgE- mediated response to inhaled and/or food allergens. FeNO (ppb) was measured off-line by the chemoluminescence method on samples obtained from gas collected in a balloon during tidal breathing. RESULTS: There was a significant difference between the AVB/AD (23.4 +/- 14.3 ppb, n=15) vs the AVB without AD group (13.5 +/- 10. 1 ppb, n=13) or the AD without AVB group (11.0 +/- 8.3 ppb, n=14). Maternal feeding for more than 2 months decreased FeNO by 50%. CONCLUSION: Atopic children below 2 years with AD produce more NO after AVB than non-atopic children or atopic children without any history of AVB. Maternal feeding decreases FeNO.

[Assessment of the handling of inhaler devices: an observational study of children in primary care]. / Comparaison de l'utilisation des dispositifs d'inhalation par les enfants asthmatiques en pratique de ville.

UNLABELLED: The correct use of inhaler devices is important for the efficacy of the treatment of childhood asthma. Few studies have compared the use of inhaler devices in real life, in particular in children. AIM: To determine whether such devices were correctly used in asthmatic children within a primary care setting. POPULATION AND METHODS: Three hundred and sixty-four children aged 5 to 18 years (mean+/-SD: 14.1+/-3.3) treated for at least 1 month by an inhaler device were included. During a routine visit to the doctor, the primary care physician assessed the childrens' handling of their current device, using a checklist established for each device from the package leaflet. RESULTS: At least half of the patients made at least 1 error, regardless of the inhaler used. The best result was obtained with the Diskus (46% error-rate) and the worst with the pressurized metered-dose inhaler (pMDI) (78% error-rate). The rank order of increasing critical-error rate (at least 1 error) was as follows: Diskus (6%)

[Prescription of asthma action plans in the Aquitaine region of France]. / Évaluation de la prescription des plans d'actions d'asthme par les médecins d'Aquitaine.

INTRODUCTION: Although guidelines recommend the prescription of written asthma action plans (WAAP), their use remains limited. METHODS: A prospective survey was performed from 2013 to 2014. We interviewed respiratory physicians, paediatric respiratory physicians and allergologists taking care of asthmatic patients and practicing in the Aquitaine region of France, using computerized questionnaires, regarding their everyday practice in the use of WAAP. RESULTS: A total of 59/143 (41%) clinicians, with a mean age of 47 years, participated in the study. A total of 41/59 (69.5%) were using a WAAP (12 different models with very inhomogeneous contents, mostly targeting symptoms only). WAAP prescribers were younger than non-prescribers, were more often female, working mostly in the Gironde area, with mixed hospital and private-based activity, and were paediatric-respiratory physicians or respiratory physicians. The severity of asthma had little influence on WAAP prescriptions. CONCLUSION: In the Aquitaine region, prescription of WAAPs remains inadequate and shows large disparities. WAAP users are mostly younger female specialists.

[Early lung disease in infants with cystic fibrosis. Diagnostic tools and possible therapeutic pathways]. / Atteinte respiratoire précoce chez les nourrissons atteints de mucoviscidose. Outils de diagnostic et pistes pour la prise en charge.

The lungs of infants with cystic fibrosis (CF) have been considered to be normal at birth. However, recent data indicates that this is unlikely to be true in most cases. Animal CF-models developed in the early 2000s have shown that constitutional airway narrowing may be present at birth, and is associated with both functional and structural abnormalities. Longitudinal birth cohort studies have shown that 25 % of CF infants followed in specialized centers, while being asymptomatic, showed decreased lung function at 3months of age. Air trapping was present in 68 % and bronchiectasis in 28 % of patients at the same age. The presence of neutrophil elastase in the bronchoalveolar lavage at 3months of age tripled the risk of bronchiectasis at the age of 3years. Currently available tools such as infant pulmonary function tests (both the jacket and multiple breath washout) as well as high-resolution volume controlled chest-computed tomography or functional magnetic resonance imaging will facilitate early intervention trials in the very near future. The role of such tools for the routine follow-up of patients, and the ability of early therapeutic interventions to alter the natural history of CF-lung disease should soon be established.

[Early lung disease in cystic fibrosis]. / Atteinte respiratoire précoce dans la mucoviscidose.

Recent data has shown that lung inflammation and infection subvene very early in very young infants with Cystic Fibrosis (CF). This leads to impaired lung function and structural damage, even in asymptomatic children. In the CF-pig model constitutional airway narrowing is present at birth, and is associated with defective mucus migration, and impaired bacterial clearance. At the age of 3 months, 25% of screened CF infants show decreased lung function. Air trapping is also present in 68% and bronchiectasis in 28% of patients. At the same age, the presence of neutrophil elastase in the bronchoalveolar lavage is an ominous sign since it triples the risk of bronchiectasis at the age of 3 years. Since only very few drug therapies have been validated in the preschool children, adapted clinical trials are warranted in this age group. Early interventions may have a huge impact on the natural history of CF, on the condition of not interfering with normal lung growth.

Evaluation of nutritional status and support in children with congenital heart disease.

BACKGROUND/OBJECTIVES: The objective of this disease was to determine the prevalence of malnutrition in children with congenital heart disease (CHD). SUBJECTS/METHODS: A total of 125 children with CHD, under 6 months of age, were divided into four groups: no pulmonary hypertension (PH) or cyanosis (group 1, n=47), isolated cyanosis (group 2, n=52), isolated PH (group 3, n=16), and PH and cyanosis (group 4, n=10). Six children died at 6 months (n=4), 12 months (n=1) and 19 months (n=1). The remaining children were followed-up for 24 months. Prevalence of moderate to severe malnutrition (weight/weight for height <80%), caloric intake and medications were compared between the four groups. RESULTS: Moderate or severe malnutrition was more frequent in group 4 (100%) compared with others groups (group 1, 20%; group 2, 16.7% and group 3, 50%; P<0.05). Low oral caloric intake was more frequent in group 3 (71.4%) and group 4 (75%) than in group 1 (28%) and 2 (28.6%) (P<0.05). Food enrichment was practised in half of the children of group 4 and rarely in other groups (group 1, 15.8%; group 2, 8.6% and group 3, 11.1%; P<0.05). Enteral feeding was used more often in groups 3 (33.3%) and 4 (50%) than in groups 1 (15.8%) or 2 (14.3%; P<0.05). CONCLUSIONS: Moderate or severe malnutrition is present in 15% of children with CHD, and it is more frequent in case of PH. Half of these children demonstrate low caloric intake, whereas few have proper nutritional support.

[New tools in cystic fibrosis]. / Nouvelles techniques d'évaluation dans la mucoviscidose.

The use of 3 novel tools available for the diagnosis and treatment in cystic fibrosis are described here. 1) The lung clearance index is a sensitive method which can detect functional impairment in the first months after birth. 2) Detailed morphological analyses of the lung can be performed with the new MRI sequences, without any contrast medium or risk of radiation. The analysis of functional MRI data (perfusion, diffusion, ventilation, inflammation) will be possible, and these data will be correlated to morphological data. The exploration of other organs such as the sinuses, liver and abdomen during the same examination represents another definite advantage. 3) Organoïds are a good example of personalized medicine. This tool explores CFTR function and treatment response in each of the 2000 or so known CFTR mutations. These tests are limited to specialized centers, mostly within a research context. However, their generalization after standardization is expected in the near future.

[New therapeutic developments in cystic fibrosis]. / Nouvelles thérapeutiques ciblant le canal chlorure dans la mucoviscidose.

Since the discovery of chloride secretion by the Cystic Fibrosis Transport regulator CFTR in 1983, and CFTR gene in 1989, knowledge about CFTR synthesis, maturation, intracellular transfer and function has dramatically expanded. These discoveries have led to the distribution of CF mutations into 6 classes with different pathophysiological mechanisms. In this article we will explore the state of art on CFTR synthesis and its chloride secretion function. We will then explore the consequences of the 6 classes of mutations on CFTR protein function and we will describe the new therapeutic developments aiming at correcting these defects.

[Pitfalls in hemoglobin oxygen saturation measurement: a case of chronic desaturation]. / Pièges de la mesure de la saturation de l'hémoglobine en oxygène : à propos d'un cas de désaturation chronique.

The measurement of oxygen saturation by pulse oximetry (SpO2) is simple and fast. This non-invasive and widespread technique gives an indication of the oxygen level in arterial blood. While the method is reliable, there are limitations that can compromise the diagnostic procedure. The objective of the present paper is to list these limitations and discuss the precautions to be taken to optimize the interpretation of the results. Based on the case of a 3-year-old patient who presented with chronic hemoglobin oxygen desaturation, we discuss a decision-making algorithm in order to avoid unnecessary, expensive, and stressful investigations.

[National consensus regarding azithromycin use in cystic fibrosis]. / Consensus national sur la prescription de l'azithromycine dans la mucoviscidose.

AIM: To propose a formalized consensus agreement regarding the prescription of azithromycin in cystic fibrosis (CF). MATERIAL AND METHODS: Application of the Delphi method in 5 thematic fields: indications, contra-indications, dosage, precautions for use and treatment follow-up. RESULTS: Thirty identified French CF centers participated in the process on 49 (61%), which comprised 3 rounds. Experts validated azithromycin as a long-term anti-inflammatory agent in children aged over 6 years, presenting with the classical form of CF, irrespective of the bacteriological status of the patient (except for non-tuberculous mycobacteria). Azithromycin administration should not be routine in the milder forms of the disease, and avoided in the presence of severe hepatic or renal involvement. In children whose weight is below 40 kg, a strong consensus recommended a single daily oral dose, administered three times weekly. However, in adults, the level of agreement was weaker. Minimal duration of treatment is 6 months, after which the drug should be discontinued if no observable effect is noted on clinical parameters, exacerbation rate and/or FEV1. Clinical monitoring of treatment tolerance is recommended (nausea, diarrhea, skin rash, tinnitus, deafness, arthropathy), without increasing the frequency of surveillance of sputum bacteria. However, it is essential to monitor sputum for fungi (expectoration, Aspergillus, broncho-pulmonary allergic aspergillosis). CONCLUSION: This consensus statement defines an area for the prescription of azithromycin in CF, with the aim of better harmonization of its use.