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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 â0.65 difference (95% CI [â3.3 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 â0.10 (â1.3 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).
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Antibacterianos/uso terapêutico , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Progressão da Doença , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/etiologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Fatores de TempoRESUMO
Median cystic fibrosis (CF) survival has increased dramatically over time due to several factors, including greater availability and use of antimicrobial therapies. During the progression of CF lung disease, however, the emergence of multidrug antimicrobial resistance can limit treatment effectiveness, threatening patient longevity. Current planktonic-based antimicrobial susceptibility testing lacks the ability to predict clinical response to antimicrobial treatment of chronic CF lung infections. There are numerous reasons for these limitations including bacterial phenotypic and genotypic diversity, polymicrobial interactions, and impaired antibiotic efficacy within the CF lung environment. The parallels to other chronic diseases such as non-CF bronchiectasis are discussed as well as research priorities for moving forward.
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Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Fibrose Cística/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Doença Crônica/tratamento farmacológico , Fibrose Cística/microbiologia , Humanos , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Escarro/microbiologiaRESUMO
PURPOSE OF REVIEW: Evolving cystic fibrosis 'standards of care' have influenced recent cystic fibrosis clinical trial designs for new therapies; care additions/improvements will require innovative trial designs to maximize feasibility and efficacy detection. RECENT FINDINGS: Three cystic fibrosis therapeutic areas (pulmonary exacerbations, Pseudomonas aeruginosa airway infections, and reduced cystic fibrosis transmembrane conductance regulator [CFTR] protein function) differ with respect to the duration for which recognized 'standards of care' have been available. However, developers of new therapies in all the three areas are affected by similar challenges: standards of care have become so strongly entrenched that traditional placebo-controlled studies in cystic fibrosis populations likely to benefit from newer therapies have become less and less feasible. Today, patients/clinicians are more likely to entertain participation in active-comparator trial designs, that have substantial challenges of their own. Foremost among these are the selection of 'valid' active comparator(s), estimation of a comparator's current clinical efficacy (required for testing noninferiority hypotheses), and effective blinding of commercially available comparators. SUMMARY: Recent and future cystic fibrosis clinical trial designs will have to creatively address this collateral result of successful past development of effective cystic fibrosis therapies: patients and clinicians are much less likely to accept simple, placebo-controlled studies to evaluate future therapies.
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Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Antibacterianos/uso terapêutico , Benzodioxóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Fibrose Cística/tratamento farmacológico , Quinolonas/uso terapêutico , Padrão de Cuidado , Pesquisa Comparativa da Efetividade/métodos , Fibrose Cística/complicações , Progressão da Doença , Combinação de Medicamentos , Humanos , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/etiologia , Resultado do TratamentoRESUMO
Cystic fibrosis (CF) is characterized by chronic infection and inflammation of the airways. In vitro culture of select bacterial species from respiratory specimens has been used to guide antimicrobial therapy in CF for the past few decades. More recently, DNA sequence-based, culture-independent approaches have been used to assess CF airway microbiology, although the role that these methods will (or should) have in routine microbiologic analysis of CF respiratory specimens is unclear. We performed DNA sequence analyses to detect bacterial species in 945 CF sputum samples that had been previously analyzed by selective CF culture. We determined the concordance of results based on culture and sequence analysis, highlighting the comparison of the results for the most prevalent genera. Although overall prevalence rates were comparable between the two methods, results varied by genus. While sequence analysis was more likely to detect Achromobacter, Stenotrophomonas, and Burkholderia, it was less likely to detect Staphylococcus. Streptococcus spp. were rarely reported in culture results but were the most frequently detected species by sequence analysis. A variety of obligate and facultative anaerobic species, not reported by culture, was also detected with high prevalence by sequence analysis. Sequence analysis indicated that in a considerable proportion of samples, taxa not reported by selective culture constituted a relatively high proportion of the total bacterial load, suggesting that routine CF culture may underrepresent significant segments of the bacterial communities inhabiting CF airways.
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Bactérias/classificação , Bactérias/isolamento & purificação , Infecções Bacterianas/microbiologia , Técnicas Bacteriológicas/métodos , Fibrose Cística/complicações , Técnicas de Diagnóstico Molecular/métodos , Infecções Respiratórias/microbiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto JovemRESUMO
OBJECTIVE: To evaluate several alternative measures of forced expiratory volume in 1 second percent predicted (FEV1 %pred) variability as potential predictors of future FEV1 %pred decline in patients with cystic fibrosis. STUDY DESIGN: We included 13,827 patients age ≥6 years from the Epidemiologic Study of Cystic Fibrosis 1994-2002 with ≥4 FEV1 %pred measurements spanning ≥366 days in both a 2-year baseline period and a 2-year follow-up period. We predicted change from best baseline FEV1 %pred to best follow-up FEV1 %pred and change from baseline to best in the second follow-up year by using multivariable regression stratified by 4 lung-disease stages. We assessed 5 measures of variability (some as deviations from the best and some as deviations from the trend line) both alone and after controlling for demographic and clinical factors and for the slope and level of FEV1 %pred. RESULTS: All 5 measures of FEV1 %pred variability were predictive, but the strongest predictor was median deviation from the best FEV1 %pred in the baseline period. The contribution to explanatory power (R(2)) was substantial and exceeded the total contribution of all other factors excluding the FEV1 %pred rate of decline. Adding the other variability measures provided minimal additional value. CONCLUSIONS: Median deviation from the best FEV1 %pred is a simple metric that markedly improves prediction of FEV1 %pred decline even after the inclusion of demographic and clinical characteristics and the FEV1 %pred rate of decline. The routine calculation of this variability measure could allow clinicians to better identify patients at risk and therefore in need of increased intervention.
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Fibrose Cística/fisiopatologia , Volume Expiratório Forçado , Pulmão/fisiopatologia , Criança , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , Fatores de TempoRESUMO
The structure and dynamics of bacterial communities in the airways of persons with cystic fibrosis (CF) remain largely unknown. We characterized the bacterial communities in 126 sputum samples representing serial collections spanning 8-9 y from six age-matched male CF patients. Sputum DNA was analyzed by bar-coded pyrosequencing of the V3-V5 hypervariable region of the 16S rRNA gene, defining 662 operational taxonomic units (OTUs) from >633,000 sequences. Bacterial community diversity decreased significantly over time in patients with typically progressive lung disease but remained relatively stable in patients with a mild lung disease phenotype. Antibiotic use, rather than patient age or lung function, was the primary driver of decreasing diversity. Interpatient variability in community structure exceeded intrapatient variability in serial samples. Antibiotic treatment was associated with pronounced shifts in community structure, but communities showed both short- and long-term resilience after antibiotic perturbation. There was a positive correlation between OTU occurrence and relative abundance, with a small number of persistent OTUs accounting for the greatest abundance. Significant changes in community structure, diversity, or total bacterial density at the time of pulmonary exacerbation were not observed. Despite decreasing community diversity in patients with progressive disease, total bacterial density remained relatively stable over time. These findings show the critical relationship between airway bacterial community structure, disease stage, and clinical state at the time of sample collection. These features are the key parameters with which to assess the complex ecology of the CF airway.
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Bactérias/crescimento & desenvolvimento , Fibrose Cística/microbiologia , Pulmão/microbiologia , Pulmão/patologia , Adolescente , Adulto , Envelhecimento/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bactérias/classificação , Bactérias/efeitos dos fármacos , Carga Bacteriana/efeitos dos fármacos , Biodiversidade , Fibrose Cística/tratamento farmacológico , Fibrose Cística/fisiopatologia , Progressão da Doença , Humanos , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Masculino , Metagenoma/efeitos dos fármacos , Análise de Componente Principal , Testes de Função Respiratória , Escarro/efeitos dos fármacos , Escarro/microbiologia , Adulto JovemRESUMO
OBJECTIVE: To characterize spirometry and height changes in cohorts of 6-year-old children with cystic fibrosis (CF). STUDY DESIGN: Global Lung Initiative forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC, and the Centers for Disease Control and Prevention height-for-age (HFA) z-scores were generated for 6-year-old children from the Cystic Fibrosis Foundation Patient Registry each year between 1994 and 2012. Z-score mean differences were analyzed by the t test, and time trends of means were analyzed by least squares regression for all children and for subgroups of sex, F508del mutation genotype, Medicaid insurance, and prenatal/newborn screening identification. Z-score distributions were compared using the 2-sample Kolmogorov-Smirnov test. RESULTS: A total of 11â670 children with CF were studied, of whom 50.5% were males, 50.2% had the F508del/F508del genotype, and 46.6% were insured by Medicaid. Mean HFA, FEV1, and FVC z-scores increased significantly over the period in the entire cohort and in all subgroups (P < .001), but FEV1/FVC z-scores were below normal and did not change significantly. In 2012, children identified by screening had significantly higher mean HFA (P = .002), FEV1 (P < .001), and FVC (P < .001) z-scores compared with children not screened, with 90% of FVC and 71.4% of FEV1z-scores greater than predicted by the normal distribution. FEV1/FVC z-scores were not different between the children who were and were not screened. CONCLUSION: Consistent, significant increases in HFA, FEV1, and FVC occurred between 1994 and 2012, but FEV1/FVC, a measure of airway obstruction, did not change appreciably during this period. FVC and FEV1z-score distributions suggest that normative equation reference populations underpredict lung volumes of children with CF, but the reasons for this remain unclear.
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Estatura , Fibrose Cística/fisiopatologia , Pulmão/fisiopatologia , Criança , Feminino , Volume Expiratório Forçado , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Triagem Neonatal , Espirometria , Capacidade VitalRESUMO
Antibiotics are frequently utilized for cystic fibrosis (CF)-related pulmonary exacerbation treatment. The antibiotic spectrum index (ASI) is an antimicrobial stewardship tool developed to compare the relative breadth of individual antibiotics. This study aimed to create two expanded CF-specific ASI scoring indices for use in antimicrobial stewardship research and clinical care. The first scoring index expanded the original ASI to include bacterial microorganisms common to CF airway infections (CF-ASI). The second scoring system only included scores for bacterial microorganisms classically identified in CF airway infections (CF-sASI). Sixty-two antibiotics were evaluated and included in the updated ASIs. When multiple antibiotics are prescribed, we proposed using an additive ASI approach whereby the sum of the individual prescribed antibiotic scores represents the total ASI score. The application of CF-focused ASIs into CF research and stewardship programs can help to optimize antibiotic benefits, minimize harms and allow for increased sustainability of antibiotic use in CF.
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Rationale: Rates of viral respiratory infection (VRI) are similar in people with cystic fibrosis (CF) and the general population; however, the associations between VRI and CF pulmonary exacerbations (PEx) require further elucidation.Objectives: To determine VRI prevalence during CF PEx and evaluate associations between VRI, clinical presentation, and treatment response.Methods: The STOP2 (Standardized Treatment of Pulmonary Exacerbations II) study was a multicenter randomized trial to evaluate different durations of intravenous antibiotic therapy for PEx. In this ancillary study, participant sputum samples from up to three study visits were tested for respiratory viruses using multiplex polymerase chain reactions. Baselines and treatment-associated changes in mean lung function (percent predicted forced expiratory volume in 1 s), respiratory symptoms (Chronic Respiratory Infection Symptom Score), weight, and C-reactive protein were compared as a function of virus detection. Odds of PEx retreatment within 30 days and future PEx hazard were modeled by logistic and Cox proportional hazards regression, respectively.Results: A total of 1,254 sputum samples from 621 study participants were analyzed. One or more respiratory viruses were detected in sputum samples from 245 participants (39.5%). Virus-positive participants were more likely to be receiving CF transmembrane conductance regulator modulator therapy (45% vs. 34%) and/or chronic azithromycin therapy (54% vs. 44%) and more likely to have received treatment for nontuberculous Mycobacterium infection in the preceding 2 years (7% vs. 3%). At study visit 1, virus-positive participants were more symptomatic (mean Chronic Respiratory Infection Symptom Score, 53.8 vs. 51.1), had evidence of greater systemic inflammation (log10 C-reactive protein concentration, 1.32 log10 mg/L vs. 1.23 log10 mg/L), and had a greater drop in percent predicted forced expiratory volume in 1 second from the prior 6-month baseline (5.8 vs. 3.6). Virus positivity was associated with reduced risk of future PEx (hazard ratio, 0.82; 95% confidence interval, 0.69-0.99; P = 0.034) and longer median time to next PEx (255 d vs. 172 d; P = 0.021) compared with virus negativity.Conclusions: More than one-third of STOP2 participants treated for a PEx had a positive test result for a respiratory virus with more symptomatic initial presentation compared with virus-negative participants, but favorable long-term outcomes. More refined phenotyping of PEx, taking VRIs into account, may aid in optimizing personalized management of PEx.Clinical trial registered with www.clinicaltrials.gov (NCT02781610).
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Fibrose Cística , Infecções Respiratórias , Viroses , Vírus , Humanos , Fibrose Cística/complicações , Fibrose Cística/epidemiologia , Fibrose Cística/diagnóstico , Proteína C-Reativa , Prevalência , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/diagnóstico , Viroses/complicações , Viroses/epidemiologia , Viroses/diagnóstico , Antibacterianos/uso terapêuticoRESUMO
CF registry pulmonary exacerbation (PEx) analyses have employed "before and after" spirometry recovery, where the best percent predicted forced expiratory volume in 1 s (ppFEV1) prior to PEx ("baseline") is compared to the best ppFEV1 <3 months post-PEx. This methodology lacks comparators and ascribes recovery failure to PEx. Herein, we describe 2014 CF Foundation Patient Registry PEx analyses including a comparator: recovery around nonPEx events, birthdays. 49.6% of 7357 individuals with PEx achieved baseline ppFEV1 recovery while 36.6% of 14,141 achieved baseline recovery after birthdays; individuals with both PEx and birthdays were more likely to recover baseline after PEx than after birthdays (47% versus 34%); mean ppFEV1 declines were 0.3 (SD=9.3) and 3.1 (9.3), respectively. Post-event measure number had more effect on baseline recovery than did real ppFEV1 loss in simulations, suggesting that PEx recovery analyses lacking comparators are prone to artifact and poorly describe PEx contributions to disease progression.
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Fibrose Cística , Humanos , Recuperação de Função Fisiológica , Fibrose Cística/tratamento farmacológico , Pulmão , Volume Expiratório Forçado , Progressão da Doença , Antibacterianos/uso terapêuticoRESUMO
RATIONALE: Pulmonary exacerbations (PEx) remain the most common cause of morbidity, recurrent hospitalization and diminished survival in people with CF (PWCF), and are characterized by excess inflammation. Corticosteroids are potent, widely available anti-inflammatory drugs. However, corticosteroid efficacy data from randomized controlled trials (RCTs) in PWCF are limited. OBJECTIVES: To determine whether adjunctive systemic corticosteroid therapy is associated with improved outcomes in acute CF PEx. METHODS: We performed a secondary analysis of STOP2, a large multicenter RCT of antimicrobial treatment durations for adult PWCF presenting with PEx, that included the use of corticosteroids as a stratification criterion in its randomization protocol. Corticosteroid treatment effects were determined after propensity score-matching for covariates including age, sex, baseline FEV1, genotype and randomization arm. The primary outcome measure was the change in percent predicted FEV1 (ppFEV1). Symptoms, time to next PEx and the incidence of adverse events (AEs) and serious adverse events (SAEs) were assessed as secondary endpoints. Phenotypic factors associated with the clinical decision to prescribe steroids were also investigated. RESULTS: Corticosteroids were prescribed for 168 of 982 PEx events in STOP2 (17%). Steroid prescription was associated with decreased baseline ppFEV1, increased age, and female sex. Co-treatment with corticosteroids was independent of treatment arm allocation, and did not result in greater mean ppFEV1 response, longer median time to next PEx or more substantial symptomatic improvement compared to propensity-matched PWCF receiving antibiotics alone. AEs were not increased in corticosteroid-treated PWCF. The total number of SAEs - but not the number of corticosteroid-related or PEx-ralated SAEs - was higher among patients receiving corticosteroids. CONCLUSION: Empiric, physician-directed treatment with systemic corticosteroids, while common, is not associated with improved clinical outcomes in PWCF receiving antibiotics for PEx.
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BACKGROUND: Pulmonary exacerbations (PEx) remain a major cause of morbidity and mortality in people with cystic fibrosis (PWCF). Although the combination cystic fibrosis transmembrane conductance regulator (CFTR) modulators lumacaftor/ivacaftor and tezacaftor/ivacaftor have been shown to reduce PEx frequency, their influence on clinical and biochemical responses to acute PEx treatment is unknown. METHODS: We performed a secondary analysis of STOP2, a large multicenter randomized controlled trial of antimicrobial treatment durations for adult PWCF presenting with PEx. Propensity score matching was used to compare outcomes in antibiotic-treated F508del/F508del PWCF receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor with those observed in antibiotic-treated F508del/F508del controls not receiving CFTR modulator therapy. The primary outcome measure was the change in percent predicted FEV1 (ppFEV1) following completion of intravenous (IV) antibiotics, with post-antibiotic changes in symptoms, serum C-reactive protein (CRP) concentrations and weight included as secondary endpoints. RESULTS: Among 982 PEx events in randomized PWCF, 480 were homozygous for F508del, of whom 289 were receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor at initiation of antibiotic therapy. Modulator-treated F508del/F508del PWCF did not demonstrate greater improvements in ppFEV1, symptoms, serum CRP or weight following antibiotic treatment compared to modulator-naïve controls matched for age, sex, baseline ppFEV1, genotype, body mass index, initial CRP, initial symptoms, exacerbation history, diabetic status, randomization arm and concomitant medical therapy. CONCLUSION: In the acute setting, CFTR modulator therapy with lumacaftor/ivacaftor or tezacaftor/ivacaftor does not convey additional clinical or biochemical advantage above standardized PEx treatment in F508del/F508del PWCF.
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Fibrose Cística , Adulto , Feminino , Humanos , Masculino , Aminofenóis/uso terapêutico , Antibacterianos/uso terapêutico , Benzodioxóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/uso terapêutico , Combinação de Medicamentos , Mutação , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Cystic fibrosis (CF) pulmonary exacerbations (PEx) are clinical events that commonly result in increased treatment burden, decreased quality of life, and accelerated lung disease progression. CF PEx have historically been approached as though dealing with acute infections, and antibiotic treatments have been associated with improved outcomes. In this review, we discuss data supporting a causal role of CF airway infection in PEx as well studies that highlight our knowledge gaps in regard to PEx definitions, pathophysiology, and optimal treatment approaches. In the era of highly effective cystic fibrosis transmembrane conductance regulator modulator therapy, and the continually increasing health and longevity of persons with CF, a better understanding of PEx and further optimization of PEx antibiotic treatment approaches are needed.
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Fibrose Cística , Antibacterianos/uso terapêutico , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Humanos , Pulmão , Qualidade de Vida , TóraxRESUMO
Chronic polymicrobial airway infections are a hallmark of cystic fibrosis (CF) lung disease. Antibiotic therapy is a primary treatment of CF pulmonary exacerbations (PEx); however, the impact of episodic antibiotic treatment on airway bacterial communities has not been well described. We analyzed sputum samples from adults with CF obtained immediately before and during antibiotic treatment of PEx. Sequencing of the V4 region of the bacterial 16S ribosomal RNA gene was used to assess changes in bacterial community structure during antibiotic treatment. The peak impact of antibiotic treatment was observed by day four or five of treatment. These findings advance our understanding of bacterial community dynamics during antibiotic treatment of PEx and complement recent and ongoing studies evaluating the optimal duration of antibiotic therapy for PEx.
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Fibrose Cística , Adulto , Antibacterianos/uso terapêutico , Bactérias , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Fibrose Cística/microbiologia , Humanos , Pulmão , RNA Ribossômico 16S , Escarro/microbiologiaRESUMO
BACKGROUND: The purpose of these analyses was to determine whether overall costs were reduced in cystic fibrosis (CF) patients experiencing pulmonary exacerbation (PEx) who received shorter versus longer durations of treatment. METHODS: Among people with CF experiencing PEx, we calculated 30-day inpatient, outpatient, emergency room, and medication costs and summed these to derive total costs in 2020 USD. Using the Kaplan-Meier sample average (KMSA) method, we calculated adjusted costs and differences in costs within two pairs of randomized groups: early robust responders (ERR) randomized to receive treatment for 10 days (ERR-10 days) or 14 days (ERR-14 days), and non-early robust responders (NERR) randomized to receive treatment for 14 days (NERR-14 days) or 21 days (NERR-21 days). RESULTS: Patients in the shorter treatment duration groups had shorter lengths of stay per hospitalization (mean ± standard deviation (SD) for ERR-10 days: 7.9 ± 3.0 days per hospitalization compared to 10.1 ± 4.2 days in ERR-14 days; for NERR-14 days: 8.7 ± 4.9 days per hospitalization compared to 9.6 ± 6.5 days in NERR-21 days). We found statistically significantly lower adjusted mean costs (95% confidence interval) among those who were randomized to receive shorter treatment durations (ERR-10 days: $60,800 ($59,150 - $62,430) vs $74,420 ($72,610 - $76,450) in ERR-14 days; NERR-14 days: $66,690 ($65,960-$67,400) versus $74,830 ($73,980-$75,650) in NERR-21 days). CONCLUSIONS: Tied with earlier evidence that shorter treatment duration was not associated with worse clinical outcomes, our analyses indicate that treating with shorter antimicrobial durations can reduce costs without diminishing clinical outcomes.
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Fibrose Cística , Antibacterianos/uso terapêutico , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Custos de Cuidados de Saúde , Hospitalização , Humanos , PulmãoRESUMO
BACKGROUND: Cystic fibrosis (CF) pulmonary exacerbations can be serious respiratory events and reduction in exacerbation rate or risk are important efficacy endpoints for CF therapeutic trials. Variability in exacerbation diagnoses and treatment have led drug developers to employ "objective" exacerbation definitions combining antimicrobial treatment (AT) and the presence of ≥4 of 12 respiratory criteria (first published by Fuchs et al. [NEJM 1994;331(10):637-42]). Assumptions underlying this approach have yet to be formally evaluated. METHODS: Respiratory events (RE) observed during a 48-week trial of ataluren (NCT02139306), a read-through agent for premature nonsense codons, were compared across six exacerbation definitions: any AT, intravenous AT (IVAT), ≥4 Fuchs criteria present, AT plus ≥4 Fuchs criteria, IVAT plus ≥4 Fuchs criteria, and investigator assessment. Fuchs definitions were evaluated by assessing missingness of individual criteria and associations between criteria presence and clinician exacerbation assessment. RESULTS: Among 751 RE, more than one third had ≥4 Fuchs criteria present but were not assessed as exacerbations by investigators. Data for ≥1 and for 4 Fuchs criteria, respectively, were missing for ~ 90% and >30% of RE. Only 6/12 Fuchs criteria were present more often when investigators assessed RE as exacerbations than when they did not. CONCLUSIONS: "Objective" definitions have shortcomings inconsistent with their purpose of optimizing exacerbation capture in clinical trials : 1) they capture events clinicians do not consider exacerbations, 2) are prone to data missingness which can bias the likelihood of meeting the definition, and 3) employ criteria that are not associated with investigator assessment of exacerbation.