Change in circulating proteins during treatment of pulmonary exacerbation in patients with cystic fibrosis.
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ABSTRACT:
SUBMITTER: Wagner BD
PROVIDER: S-EPMC7875569 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
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Change in circulating proteins during treatment of pulmonary exacerbation in patients with cystic fibrosis.
Wagner Brandie D BD Berkalieva Asem A Borges Monica M Fleming Grant G Graham Noah N Peterson Emily E Jin Xin X Zemanick Edith T ET
Health science reports 20210210 1
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Project description:BackgroundMost studies of pulmonary exacerbations (PEx) in cystic fibrosis (CF) focus on intravenous (IV)-treated PEx, though most PEx are treated with oral antibiotics. Our objectives were to describe predictors of antibiotic choice and outcomes for PEx initially identified in clinic.MethodsFor each patient in the U.S. CF Foundation Patient Registry, we selected the first PEx recorded at a clinic visit in 2013-14 following a clinic visit without a PEx. We used multivariable logistic regression to determine associations between clinical characteristics and antibiotic treatment choice. We determined outcomes in the 90 days after the first PEx.ResultsAmong 14,265 patients with a PEx initially identified in clinic, 21.4% received no antibiotics, 61.5% received new oral and/or inhaled antibiotics, and 17.0% had IV antibiotics within 14 days. Compared to IV antibiotics, patients more likely to receive new oral and/or inhaled antibiotics: were male, <13 years old, had BMI >10th percentile or 18.5 kg/m2, >90 days between clinic visits, FEV1 > 70% predicted at the PEx, no prior-year IV-treated PEx, FEV1 decline <10% predicted, and private insurance. Following the PEx, 30.3% of patients had no clinical encounters within 90 days. Treatment with IV antibiotics within 90 days occurred for 23.7% treated without antibiotics, 22.8% of new oral and/or inhaled antibiotics, and 27.1% of IV antibiotics.ConclusionMost PEx identified in clinic are treated with new oral and/or inhaled antibiotics. Markers of disease severity are associated with antibiotic treatment choice. Many patients had no follow-up evaluation within 90 days of treatment.
| S-EPMC6940539 | biostudies-literature
Project description:Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc ) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (Vθ) normalized by the median observed value (Vc = Vθ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CLθ × CRCL), where CLNR represents nonrenal clearance and CLθ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: Vθ, 4.92 ± 0.76 liters · kg-1; CLNR, 0.59 ± 0.30 liters · h-1; CLθ, 5.97 × 10-3 ± 1.24 × 10-3; Vp (volume of the peripheral compartment), 3.77 ± 1.41 liters; Q (intercompartmental clearance), 4.08 ± 2.17 liters · h-1 The free area under the concentration-time curve (fAUC) values for 7.5 and 10 mg/kg were 30 ± 4.6 and 52 ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter-1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.).
| S-EPMC7187619 | biostudies-literature
Project description:Previous studies indicate that hospital rather than home treatment of pulmonary exacerbations (PEx) in people with cystic fibrosis (CF) can improve outcomes. We evaluated characteristics of adult participants from the Standardized Treatment of Pulmonary Exacerbations (STOP2) trial with two separate comparisons: (1) those who were treated initially in hospital (N = 768) to those treated initially at home (N = 214) and (2) those treated only in hospital (N = 328) to those who were treated only at home or both at home and in hospital (N = 654). Participants who had Medicaid insurance, were treated for shorter duration, and traveled longer to reach treatment centers were more likely to have been treated initially in the hospital. Having Medicaid insurance, being treated for a shorter duration, and being male were associated with being treated only in the hospital. This analysis suggests decisions about the location of treatment are based on pragmatic factors rather than on clinical characteristics.
| S-EPMC10995101 | biostudies-literature
Project description:BackgroundThe airways of patients with cystic fibrosis (pwCF) harbour complex fungal and bacterial microbiota involved in pulmonary exacerbations (PEx) and requiring antimicrobial treatment. Descriptive studies analysing bacterial and fungal microbiota concomitantly are scarce, especially using both culture and high-throughput-sequencing (HTS).ObjectivesWe analysed bacterial-fungal microbiota and inter-kingdom correlations in two French CF centres according to clinical parameters and antimicrobial choices.MethodsForty-eight pwCF with PEx from Creteil (n = 24) and Lille (n = 24) CF centres were included over 2 years. Sputa were collected for culture and targeted-HTS (ITS2 and V3-V4 targets). Sequencing and culture data, along with clinical, radiological and treatment data, were analysed. Two-level stratified analysis was performed to study potential confounding factors (age, CF mutation, FEV1 and antibiotics) on the centre factor. Inter-kingdom correlations were analysed.ResultsSignificant differences in the bacterial microbiota profile were found between centres (p-value = 0.03). For mycobiota, the taxonomic distribution and diversity were comparable. HTS provided concordant but more detailed information than culture and increased detection of main CF fungi (> 25% more positive samples for Aspergillus or Scedosporium). FEV1 and systemic antibiotic before PEx influenced bacterial microbiota, but no clinical association was found with the mycobiota. No inter-kingdom correlation between Pseudomonas and fungi was found.ConclusionsDescribing concomitant bacterial and fungal communities of pwCF at the beginning of PEx using culture and HTS shows greater diversity in HTS and better detection in case of low microbial load. Interesting inter-kingdom correlations were observed, requiring further research on larger cohorts to understand the potential microbial interactions.
| S-EPMC11736540 | biostudies-literature
Project description:Rationale: People with cystic fibrosis (CF) experience acute worsening of respiratory symptoms and lung function known as pulmonary exacerbations. Treatment with intravenous antimicrobials is common; however, there is scant evidence to support a standard treatment duration. Objectives: To test differing durations of intravenous antimicrobials for CF exacerbations. Methods: STOP2 (Standardized Treatment of Pulmonary Exacerbations 2) was a multicenter, randomized, controlled clinical trial in exacerbations among adults with CF. After 7-10 days of treatment, participants exhibiting predefined lung function and symptom improvements were randomized to 10 or 14 days' total antimicrobial duration; all others were randomized to 14 or 21 days' duration. Measurements and Main Results: The primary outcome was percent predicted FEV1 (ppFEV1) change from treatment initiation to 2 weeks after cessation. Among early responders, noninferiority of 10 days to 14 days was tested; superiority of 21 days compared with 14 days was compared for the others. Symptoms, weight, and adverse events were secondary. Among 982 randomized people, 277 met improvement criteria and were randomized to 10 or 14 days of treatment; the remaining 705 received 21 or 14 days of treatment. Mean ppFEV1 change was 12.8 and 13.4 for 10 and 14 days, respectively, a ‒0.65 difference (95% CI [‒3.3 to 2.0]), excluding the predefined noninferiority margin. The 21- and 14-day arms experienced 3.3 and 3.4 mean ppFEV1 changes, a difference of ‒0.10 (‒1.3 to 1.1). Secondary endpoints and sensitivity analyses were supportive. Conclusions: Among adults with CF with early treatment improvement during exacerbation, ppFEV1 after 10 days of intravenous antimicrobials is not inferior to 14 days. For those with less improvement after one week, 21 days is not superior to 14 days. Clinical trial registered with www.clinicaltrials.gov (NCT02781610).
| S-EPMC8786075 | biostudies-literature
Project description:BackgroundGiven the variability in pulmonary exacerbation (PEx) management within and between Cystic Fibrosis (CF) Care Centers, it is possible that some approaches may be superior to others. A challenge with comparing different PEx management approaches is lack of a community consensus with respect to treatment-response metrics. In this analysis, we assess the feasibility of using different response metrics in prospective randomized studies comparing PEx treatment protocols.MethodsResponse parameters were compiled from the recent STOP (Standardized Treatment of PEx) feasibility study. Pulmonary function responses (recovery of best prior 6-month and 12-month FEV1% predicted and absolute and relative FEV1% predicted improvement from treatment initiation) and sign and symptom recovery from treatment initiation (measured by the Chronic Respiratory Infection Symptom Score [CRISS]) were studied as categorical and continuous variables. The proportion of patients retreated within 30days after the end of initial treatment was studied as a categorical variable. Sample sizes required to adequately power prospective 1:1 randomized superiority and non-inferiority studies employing candidate endpoints were explored.ResultsThe most sensitive endpoint was mean change in CRISS from treatment initiation, followed by mean absolute FEV1% predicted change from initiation, with the two responses only modestly correlated (R2=.157; P<0.0001). Recovery of previous best FEV1 was a problematic endpoint due to missing data and a substantial proportion of patients beginning PEx treatment with FEV1 exceeding their previous best measures (12.1% >12-month best, 19.6% >6-month best). Although mean outcome measures deteriorated approximately 2-weeks post-treatment follow-up, the effect was non-uniform: 62.7% of patients experienced an FEV1 worsening versus 49.0% who experienced a CRISS worsening.ConclusionsResults from randomized prospective superiority and non-inferiority studies employing mean CRISS and FEV1 change from treatment initiation should prove compelling to the community. They will need to be large, but appear feasible.
| S-EPMC6581041 | biostudies-literature
Project description:BackgroundTreatment of pulmonary exacerbations (PEx) in cystic fibrosis (CF) varies widely with no consensus on management practices or best indicators of therapeutic success. To design trials evaluating PEx treatment factors, we characterise the heterogeneity of PEx care in adults and paediatrics, and correlate it with measures of clinical response including short-term and long-term lung function changes, change in symptom severity score and time to next intravenous antibiotic therapy.MethodsData were used from a prospective observational study of patients with CF ≥10 years of age enrolled at six sites between 2007 and 2010. All were started on intravenous antibiotics for a clinically diagnosed PEx. Analysis of variance, logistic and Cox regression were used to examine the association of treatment factors with short-term and long-term clinical response.ResultsOf 123 patients with CF (60% women, aged 23.1±10.2 years), 33% experienced <10% relative improvement in FEV1 during treatment, which was associated with failing to recover baseline lung function 3 months after treatment (OR=7.8, 95% CI 1.9 to 31.6, p=0.004) and a longer time to next intravenous antibiotic (HR=0.48, 95% CI 0.27 to 0.85, p=0.011). Symptom improvement was observed but was not associated with subsequent lung function or time to next antibiotic therapy, which had a median recurrence time of 143 days.ConclusionsImmediate symptomatic or respiratory response to PEx treatment did not have a clear relationship with subsequent outcomes such as lung function or intravenous antibiotic-free interval. These results can inform future research of treatment regimens for PEx in terms of interventions and outcome measures.Trial registrationNCT00788359 (www.clinicaltrials.gov).
| S-EPMC4778725 | biostudies-literature
Project description:Rationale: Pulmonary exacerbations (PExs) are associated with significant morbidity in people with cystic fibrosis (CF). Severe PExs are treated with intravenous antibiotics, including tobramycin. CF care guidelines recommend continuing chronic maintenance medications during PEx treatment. Azithromycin (AZM) is one of the most widely prescribed chronic medications for CF in the United States. Recent evidence has identified a potential antagonistic relationship between AZM and tobramycin.Objectives: To determine whether, among PEx treated with intravenous tobramycin, concomitant AZM use is associated with worse clinical outcomes.Methods: Retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System (CFFPR-PHIS)-linked dataset. People with CF age 6-21 years were included if they were hospitalized between 2006 and 2016 for a PEx. Inverse probability of treatment weighing was used to minimize the effects of confounders, including indication bias. Associations of concomitant treatment with AZM and lung function outcomes were determined using linear mixed-effect models and generalized estimating equations. Cox proportional hazard regression models were used to evaluate associations with time to next PEx.Results: Among the 10,660 people with CF included in the CFFPR-PHIS-linked dataset, 2,294 children and adolescents with 5,022 PExs that had intravenous tobramycin use were identified. A little less than half (n = 2,247; 45%) of all PExs were treated concomitantly with AZM and intravenous tobramycin. AZM use both at the most recent outpatient clinic encounter and during PEx treatment in combination with intravenous tobramycin was associated with a significantly lower absolute improvement in percentage-predicted forced expiratory volume in 1 second (ppFEV1) (-0.93%; 95% confidence interval [CI], -1.78 to -0.07; P = 0.033), a lesser odds of returning to 90% or more of baseline ppFEV1 (odds ratio, 0.79; 95% CI, 0.68-0.93; P = 0.003), and a shorter time to next PEx requiring intravenous antibiotics (hazard ratio, 1.22; 95% CI, 1.14-1.31; P < 0.001) compared with intravenous tobramycin use without concomitant AZM.Conclusions: Concomitant AZM and intravenous tobramycin use for in-hospital PEx treatment was associated with poorer clinical outcomes than treatment with intravenous tobramycin without AZM. These results support the hypothesis that an antagonistic relationship between these two medications might exist.
| S-EPMC7869777 | biostudies-literature
Project description:BackgroundCystic fibrosis (CF) is an inherited recessive disorder characterized by recurrent and persistent pulmonary infections, resulting in lung function deterioration and early mortality.MethodsA cross-sectional study was conducted on the bacterial profile and antibiotic resistance pattern of 103 respiratory specimens from CF patients with signs of pulmonary exacerbation. Antibiotic susceptibility testing and biofilm formation of Staphylococcus aureus and Pseudomonas aeruginosa isolates were performed by the Kirby-Bauer disc diffusion method and microtiter plate assay, respectively. Molecular typing of S. aureus and P. aeruginosa isolates was carried out by spa typing and repetitive extragenic palindromic element PCR.ResultsIn a total of 129 isolates, the most prevalent organisms were S. aureus (55.3%) and P. aeruginosa (41.7%). Other less prevalent bacterial isolates include coagulase-negative staphylococci, Escherichia coli, klebsiella spp., Enterobacter spp., and Achromobacter xylosoxidans. The highest rate of resistance for S. aureus was observed to azithromycin and erythromycin (80%), ciprofloxacin (52.3%), clindamycin (44.6%) and tetracycline (43%). Twenty percent of S. aureus isolates were methicillin-resistant S. aureus (MRSA) and 47.6% were MDR S. aureus. For P. aeruginosa isolates the highest resistance was to cefepime (38.3%) and levofloxacin (33.3%) and 20% showed MDR phenotype.ConclusionOur study demonstrated a significant decline in the prevalence of P. aeruginosa infections in comparison to previous studies. We found S. aureus to be more prevalent in younger patients, whereas mucoid P. aeruginosa showed a shift in prevalence toward older ages. Molecular typing methods showed great diversity between isolates.
| S-EPMC9805393 | biostudies-literature
Project description:Background Antimicrobial susceptibility testing (AST) of bacterial isolates is a time- and resource-intensive procedure recommended by cystic fibrosis (CF) treatment guidelines for antimicrobial selection for pulmonary exacerbation (PEx) treatment. Methods We studied relationships between Pseudomonas aeruginosa (Pa) isolate AST results, antipseudomonal PEx treatments, and treatment responses as change in weight and percent predicted forced expiratory volume in 1 s (ppFEV1) as well as future antimicrobial treatment hazard for PEx occurring at a CF care center from 1999 through 2018. Treatments were categorized by "Pa coverage" as complete (all Pa isolates susceptible by AST to at least one administered agent), none (no isolates susceptible), incomplete (some, but not all isolates susceptible), and indeterminant (administered antipseudomonals not evaluated by AST). Weight and ppFEV1 responses were compared across Pa coverage categories using unadjusted and adjusted general estimating equations; hazard of future treatment was assessed by Cox and logistic regression. Results Among 3820 antimicrobial PEx treatment events in 413 patients with Pa, 62.6% (2390) had complete Pa coverage; 8.9% (340), 2.4% (99), and 26.2% (1000), had no, incomplete, and indeterminant Pa coverage, respectively. Mean baseline to follow-up weight change was +0.74 kg [95% CI 0.63, 0.86]; ppFEV1 change was +1.60 [1.29, 1.90]. Pa coverage category was not associated with significant differences in weight or ppFEV1 change or with future antimicrobial treatment hazard. Conclusions We did not observe superior responses for AST-defined complete Pa coverage treatments versus lesser coverage treatments, suggesting that AST may be of little utility in choosing antimicrobials for CF PEx treatment.
| S-EPMC7714709 | biostudies-literature