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Background: In children with cystic fibrosis (CF), the currently recommended amikacin dose ranges between 30 and 35 mg/kg/d; however, data supporting this dosing efficacy are lacking. In this article, the objectives were to develop a nonparametric pharmacokinetic population model for amikacin in children with CF and investigate the efficacy and toxicity at different dose rates for distinct minimum inhibitory concentration (MIC) clinical breakpoints using Monte Carlo simulations., Methods: Data from 94 children with CF (613 serum concentrations) from the Bordeaux University Hospital's CF-centre were analyzed. After determination of nonparametric pharmacokinetic population model parameters and associated influent covariates in Pmetrics, 1000 Monte Carlo simulations were performed for 7 different dose rates between 30 and 60 mg/kg/d, to predict the probability of obtaining peak serum amikacin ≥10 × MIC and trough level ≤2.5 mg/L, for MIC values between 1 and 16 mg/L., Results: The median (min-max) age and weight were 10 (0.3-17) years and 29 (6-71) kg, respectively, with only 2 children younger than 1 year of age. Body weight and creatinine clearance significantly impacted the amikacin volume of distribution and clearance. The mean relative bias/root mean squared error between observed and individual predicted concentrations was -0.68%/8.1%. Monte Carlo simulations showed that for sensitive bacteria with MICs ≤ 4, 30 mg/kg/d was most appropriate for a 100% success rate; for bacteria with MICs ≥ 8 [eg, Pseudomonas aeruginosa (MICamikacin = 8)], a dose of at least 40 mg/kg/d allowed a high success probability (90%), with a trough level below 2.5 mg/L., Conclusions: For intermediate pathogens, a dose of at least 40 mg/kg/d can improve efficacy, with an acceptable calculated residual trough level in cases of normal or hyperfiltration. Because amikacin undergoes renal clearance, which is immature until 1 year of age, dosing recommendations for this age group may be markedly high, warranting cautious interpretation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Whereas Burkholderia infections are recognized to impair prognosis in cystic fibrosis (CF) patients, there is no recommendation to date for early eradication therapy. The aim of our study was to analyse the current management of initial colonisations with Burkholderia cepacia complex (BCC) or B. gladioli in French CF Centres and its impact on bacterial clearance and clinical outcome., Methods: We performed a retrospective review of the primary colonisations (PC), defined as newly positive sputum cultures, observed between 2010 and 2018 in five CF Centres. Treatment regimens, microbiological and clinical data were collected., Results: Seventeen patients (14 with BCC, and 3 with B. gladioli) were included. Eradication therapy, using heterogeneous combinations of intravenous, oral or nebulised antibiotics, was attempted in 11 patients. Six out of the 11 treated patients, and 4 out of the 6 untreated patients cleared the bacterium. Though not statistically significant, higher forced expiratory volume in 1 second and forced vital capacity at PC and consistency of treatment with in vitro antibiotic susceptibility tended to be associated with eradication. The management of PC was shown to be heterogeneous, thus impairing the statistical power of our study. Large prospective studies are needed to define whom to treat, when, and how., Conclusions: Pending these studies, we propose, due to possible spontaneous clearance, to check the presence of Burkholderia 1 month after PC before starting antibiotics, at least in the milder cases, and to evaluate a combination of intravenous beta-lactam + oral or intravenous fluoroquinolone + inhaled aminoglycoside.

Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation. Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting. Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations. Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV 1 (ppFEV 1 ) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV 1 (+3.67%), an increase in body mass index (+0.73 kg/m 2 ), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV 1 , without improvement in body mass index or decrease in intravenous antibiotic courses. Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.

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 ±  SD) was 0.81 ± 0.30 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.

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., (Published by Elsevier Masson SAS.)

Background: We aimed to evaluate the use of central catheters introduced by a peripheral vein (PICC) in children with CF., Methods: A descriptive study in patients in whom a PICC (Beckton Dickinson) was inserted., Results: 24 children aged (median (range) 10.2 years (0.3-17.3) undergoing 44 procedures were included. PICC was successfully inserted in 93.2% (41/44) of cases. Total procedure duration was (median (range)) 32.5 (10-105) minutes. The operators encountered few difficulties, median (range) 2 (1-10) (1 (absence) to 10 (maximal)); median (range) 1 (1 to 5) attempt per child). No major side effects or infections were observed. PICC obstruction in 5 (12%) cases was successfully unblocked in 4 cases (urokinase). The catheter was functional throughout the antibiotic course in 40/41 cases. A final Doppler scan (30 cases) showed total permeability of the central veins in all cases. Satisfaction index of the operators and the patients were high: median (range) 9.5 (1-10) and 8.0 (6-10) (scale: 1 (worse) to 10 (best)), respectively., Conclusion: PICCs are simple to use, and may be safely inserted in the ward. Such catheters are well tolerated, may increase the well-being of children with CF and prove an effective means by which to deliver IV therapy in this population.