Early Detection of Cystic Fibrosis Acute Pulmonary Exacerbations in Adult and Pediatric Patients by Exhaled Breath Condensate Metabolomics.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
TISSUE(S): Breath
DISEASE(S): Cystic Fibrosis
PROVIDER: ST001164 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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Project description:With the improving survival of cystic fibrosis (CF) patients and the advent of highly effective cystic fibrosis transmembrane conductance regulator therapy, the clinical spectrum of this complex multisystem disease continues to evolve. One of the most important clinical events for patients with CF in the course of this disease is an acute pulmonary exacerbation. Clinical and microbial epidemiology studies of CF pulmonary exacerbations continue to provide important insight into the disease course, prognosis, and complications. This work has now led to a number of large scale clinical trials with the goal of improving the treatment paradigm for CF pulmonary exacerbation. The primary goal of this review is to provide a summary of the pathophysiology, the clinical epidemiology, microbial epidemiology, outcome and the treatment of CF pulmonary exacerbation.
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Project description:Ceftolozane-tazobactam has potent activity against Pseudomonas aeruginosa, a pathogen associated with cystic fibrosis (CF) acute pulmonary exacerbations (APE). Due to the rapid elimination of many antibiotics, CF patients frequently have altered pharmacokinetics. In this multicenter, open-label study, we described the population pharmacokinetics and safety of ceftolozane-tazobactam at 3 g every 8 h (q8h) in 20 adult CF patients admitted with APE. Population pharmacokinetics were determined using the nonparametric adaptive grid program in Pmetrics for R. A 5,000-patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for the ceftolozane component at 1.5 g and 3 g of ceftolozane-tazobactam q8h across a range of MICs using a primary threshold exposure of 60% free time above the MIC (fT>MIC). In these 20 adult CF patients, ceftolozane and tazobactam concentration data were best described by 2-compartment models, and ceftolozane clearance (CL) was significantly correlated with creatinine clearance (r = 0.71, P < 0.001). These data suggest that ceftolozane and tazobactam clearance estimates in CF patients are similar to those in adults without CF (ceftolozane CF CL, 4.76 ± 1.13 liter/h; tazobactam CF CL, 20.51 ± 4.41 liter/h). However, estimates of the volume of the central compartment (Vc) were lower than those for adults without CF (ceftolozane CF Vc, 7.51 ± 2.05 liters; tazobactam CF Vc, 7.85 ± 2.66 liters). Using a threshold of 60% fT>MIC, ceftolozane-tazobactam regimens of 1.5 g and 3 g q8h should achieve PTAs of ≥90% at MICs up to 4 and 8 μg/ml, respectively. Ceftolozane-tazobactam at 3 g q8h was well tolerated. These observations support additional studies of ceftolozane-tazobactam for Pseudomonas aeruginosa APE in CF patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02421120.).
| S-EPMC5075062 | biostudies-literature
Project description:Cystic fibrosis (CF) lung disease is characterized by infection, inflammation, lung function decline, and intermittent pulmonary exacerbations. However, the link between pulmonary exacerbation and lung disease progression remains unclear. Global metabolomic profiling can provide novel mechanistic insight into a disease process in addition to putative biomarkers for future study. Our objective was to investigate how the plasma metabolomic profile changes between CF pulmonary exacerbation and a clinically well state.Plasma samples and lung function data were collected from 25 CF patients during hospitalization for a pulmonary exacerbation and during quarterly outpatient clinic visits. In collaboration with Metabolon, Inc., the metabolomic profiles of matched pair plasma samples, one during exacerbation and one at a clinic visit, were analyzed using gas and liquid chromatography coupled with mass spectrometry. Compounds were identified by comparison to a library of standards. Mixed effects models that controlled for nutritional status and lung function were used to test for differences and principal components analysis was performed.Our population had a median age of 27 years (14-39) and had a median FEV1 % predicted of 65% (23-105%). 398 total metabolites were identified and after adjustment for confounders, five metabolites signifying perturbations in nucleotide (hypoxanthine), nucleoside (N4-acetylcytidine), amino acid (N-acetylmethionine), carbohydrate (mannose), and steroid (cortisol) metabolism were identified. Principal components analysis provided good separation between the two clinical phenotypes.Our findings provide putative metabolite biomarkers for future study and allow for hypothesis generation about the pathophysiology of CF pulmonary exacerbation.
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Project description:BackgroundSeveral clinical trials have shown the efficacy of continuous infusion beta-lactam (BL) antibiotics in patients with cystic fibrosis (CF); however, little is known about pharmacokinetic changes during the treatment of an acute pulmonary exacerbation (APE). Identifying and understanding these changes may assist in optimizing antibiotic dosing during APE treatment.MethodsThis study was a retrospective cohort study of 162 adult patients with CF admitted to the University of Utah Hospital between January 1, 2008, and May 15, 2014, for treatment of an APE with both a continuous infusion BL and IV tobramycin. We extracted the administered doses of continuous infusion BLs and tobramycin along with serum drug concentrations and calculated medication clearance rates. The primary outcome was change in clearance rates of continuous infusion BLs between day 2 and day 7 of APE treatment.ResultsThe BL clearance rate increased 20.7% (95% CI, 11.42 to 32.49; P < .001), whereas the tobramycin clearance rate decreased 6.3% (95% CI, -12.29 to -4.45; P < .001). The mean percent predicted FEV1 increased between admission and discharge by 12.2% (95% CI, -13.81 to -10.55; P < .001).ConclusionsClinicians should monitor BL levels along with aminoglycoside levels and make dose adjustments to maximize the chance of optimal antibiotic treatment. Continuous infusion BL and tobramycin clearance can change dramatically during the treatment of an APE, which may necessitate significant changes in dosing to achieve optimal antibiotic levels. Clearance rates of these antibiotics may change in opposite directions, requiring specific monitoring of each medication.
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Project description:Background. Cystic fibrosis (CF) is a genetic disease that results in chronic infections of the lungs. CF patients experience intermittent pulmonary exacerbations (CFPE) that are associated with poor clinical outcomes. CFPE involves an increase in disease symptoms requiring more aggressive therapy. Methods. Longitudinal sputum samples were collected from 11 patients (n = 44 samples) to assess the effect of exacerbations on the sputum metabolome using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The data was analyzed with MS/MS molecular networking and multivariate statistics. Results. The individual patient source had a larger influence on the metabolome of sputum than the clinical state (exacerbation, treatment, post-treatment, or stable). Of the 4,369 metabolites detected, 12% were unique to CFPE samples; however, the only known metabolites significantly elevated at exacerbation across the dataset were platelet activating factor (PAF) and a related monacylglycerophosphocholine lipid. Due to the personalized nature of the sputum metabolome, a single patient was followed for 4.2 years (capturing four separate exacerbation events) as a case study for the detection of personalized biomarkers with metabolomics. PAF and related lipids were significantly elevated during CFPEs of this patient and ceramide was elevated during CFPE treatment. Correlating the abundance of bacterial 16S rRNA gene amplicons to metabolomics data from the same samples during a CFPE demonstrated that antibiotics were positively correlated to Stenotrophomonas and Pseudomonas, while ceramides and other lipids were correlated with Streptococcus, Rothia, and anaerobes. Conclusions. This study identified PAF and other inflammatory lipids as potential biomarkers of CFPE, but overall, the metabolome of CF sputum was patient specific, supporting a personalized approach to molecular detection of CFPE onset.
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Project description:Treatment options for Achromobacter xylosoxidans are limited. Eight cystic fibrosis patients with A. xylosoxidans were treated with 12 cefiderocol courses. Pretreatment in vitro resistance was seen in 3 of 8 cases. Clinical response occurred after 11 of 12 treatment courses. However, microbiologic relapse was observed after 11 of 12 treatment courses, notably without emergence of resistance.
| S-EPMC8678443 | biostudies-literature
Project description:The serum pharmacokinetic profile of intravenous (i.v.) tobramycin administration was characterized for a sample of nine adult patients with cystic fibrosis (CF) who were hospitalized for an acute pulmonary exacerbation. Current recommended i.v. tobramycin dosing protocols are predicted through modeling and simulation to be suboptimal. Empirical tobramycin regimens of ≥15 mg/kg of body weight administered i.v. once daily should be evaluated for adult patients with CF to optimize outcomes.
| S-EPMC3811436 | biostudies-literature
Project description:BackgroundAlthough antimicrobial susceptibility testing (AST) frequently guides cystic fibrosis (CF) pulmonary exacerbation (PEx) management, its clinical utility is unclear. This study examined associations between AST and antimicrobial switching during PEx treatment and time and occurrence of next PEx as treatment outcomes.MethodsThis retrospective cohort study utilized Pediatric Health Information System data. Children and adolescents aged 1-18 years admitted for a PEx from 2011 to 2016 were studied. Antimicrobial switching was defined as any intra-admission change in intravenous (IV), oral, and/or inhaled antimicrobials. Time to next PEx was defined as the time between index PEx hospital discharge and subsequent hospital admission requiring IV antimicrobials. Odds of antimicrobial switching ≥5 days after treatment initiation were determined by generalized linear mixed models, and associations between AST and time to next PEx were studied using Kaplan-Meier curves and Cox proportional hazards regression.ResultsAST occurred in 2518 (39%) of 6451 PEx at 36 hospitals and was associated with increased odds of antimicrobial switching (OR 1.33, 95% CI 1.16-1.52; p = 0.001) and increased hazard of future PEx (HR 1.32, 95% CI 1.16-1.50; p < 0.001). However, antimicrobial switching was not associated with a longer time to next PEx.ConclusionsAST was associated with both increased probability of antimicrobial regimen change and increased PEx hazard. There was no evidence that antimicrobial regimen change was associated with clinical benefit as assessed by time to next PEx. However, these results indicate residual indication bias remained after adjustment for available disease covariates. Additional studies of the clinical value of AST are warranted.
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