Treatment of pulmonary exacerbations in cystic fibrosis

Bhatt, Jayesh

doi:10.1183/09059180.00006512

Cited by 127 publications

(109 citation statements)

References 127 publications

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“…episodes of acute pulmonary exacerbations (APE), whereby the overall lung function does not completely return to previous baseline values (2,3). The frequency of APE is associated with negative health outcomes, including death (2,(4)(5)(6).…”

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confidence: 99%

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Patients with Cystic Fibrosis

Bensman

Wang

Jayne

et al. 2017

Antimicrob Agents Chemother

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Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent in vitro activity against isolates recovered from CF patients, including drug-resistant strains. Altered pharmacokinetics (PK) of several betalactam antibiotics have been reported in CF patients. Therefore, this study sought to characterize the PK of CZA and perform target attainment analyses to determine the optimal treatment regimen. The PK of CZA in 12 adult CF patients administered 3 intravenous doses of 2.5 g every 8 h infused over 2 h were determined. Population modeling utilized the maximum likelihood expectation method. Monte Carlo simulations determined the probability of target attainment (PTA). An exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (fT ϾMIC ) was evaluated for ceftazidime (CAZ), and an exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds a 1-mg/liter threshold concentration (fT Ͼ1 mg/liter ) was evaluated for avibactam (AVI). Published CAZ and CZA MIC distributions were incorporated to evaluate cumulative response probabilities. CAZ and AVI were best described by one-compartment models. The values of total body clearance (CL; CAZ CL, 7.53 Ϯ 1.28 liters/h; AVI CL, 12.30 Ϯ 1.96 liters/h) and volume of distribution (V; CAZ V, 18.80 Ϯ 6.54 liters; AVI V, 25.30 Ϯ 4.43 liters) were broadly similar to published values for healthy adults. CZA achieved a PTA (fT ϾMIC , 50%) of Ͼ0.9 for MICs of Յ16 mg/liter. The overall likelihood of a treatment response was 0.82 for CZA, whereas it was 0.42 for CAZ. These data demonstrate improved pharmacodynamics of CZA in comparison with those of CAZ and provide guidance on the optimal dosing of CZA for future studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT02504827.)

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confidence: 99%

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Patients with Cystic Fibrosis

Bensman

Wang

Jayne

et al. 2017

Antimicrob Agents Chemother

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“…The ecological diversity and the dynamics of this community complicate diagnosis and treatment (Rau et al 2012). Aggressive antimicrobial therapies are typically used to treat recurrent infections (Bhatt 2013;Biller 2015), and while effective at relieving symptoms, they encourage evolutionary adaptation of bacterial populations, including the development of antimicrobial resistance (Griesenbach and Alton 2015). B. cenocepacia infection is a risk factor for CF patients (Lipuma 2010), and because it is both highly transmissible and often antibiotic resistant, its presence can exclude patients from lung transplantation (Murray et al 2008;Lobo et al 2015).…”

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confidence: 99%

Phenotypic diversity and genotypic flexibility of Burkholderia cenocepacia during long-term chronic infection of cystic fibrosis lungs

et al. 2017

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Chronic bacterial infections of the lung are the leading cause of morbidity and mortality in cystic fibrosis patients. Tracking bacterial evolution during chronic infections can provide insights into how host selection pressures-including immune responses and therapeutic interventions-shape bacterial genomes. We carried out genomic and phenotypic analyses of 215 serially collected Burkholderia cenocepacia isolates from 16 cystic fibrosis patients, spanning a period of 2-20 yr and a broad range of epidemic lineages. Systematic phenotypic tests identified longitudinal bacterial series that manifested progressive changes in liquid media growth, motility, biofilm formation, and acute insect virulence, but not in mucoidy. The results suggest that distinct lineages follow distinct evolutionary trajectories during lung infection. Pan-genome analysis identified 10,110 homologous gene clusters present only in a subset of strains, including genes restricted to different molecular types. Our phylogenetic analysis based on 2148 orthologous gene clusters from all isolates is consistent with patient-specific clades. This suggests that initial colonization of patients was likely by individual strains, followed by subsequent diversification. Evidence of clonal lineages shared by some patients was observed, suggesting inter-patient transmission. We observed recurrent gene losses in multiple independent longitudinal series, including complete loss of Chromosome III and deletions on other chromosomes. Recurrently observed loss-of-function mutations were associated with decreases in motility and biofilm formation. Together, our study provides the first comprehensive genome-phenome analyses of B. cenocepacia infection in cystic fibrosis lungs and serves as a valuable resource for understanding the genomic and phenotypic underpinnings of bacterial evolution.

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“…Although there is no consensus on the precise definition or criteria for these exacerbations, there is universal agreement that appropriate timely treatment is vital [1][2][3]. As well as acutely impacting respiratory function, these episodes have a long-term impact on lung function and survival in CF patients [2].…”

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confidence: 99%

“…Without a systematic approach to treatment durations, decisions are currently largely clinically based, and vary depending on clinician preferences, centre protocols, various patient factors and response to therapy [1]. Response to therapy is assessed using parameters such as lung function, bacterial density in sputum, oxygen saturation, weight change, inflammatory markers, symptoms and overall well-being of the patient [8].…”

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confidence: 99%