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1.
J Manag Care Spec Pharm ; 30(1): 26-33, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38153868

RESUMO

BACKGROUND: Dornase alfa and hypertonic saline are mucoactive therapies that can improve respiratory symptoms in people with cystic fibrosis (CF). A recent randomized control trial showed that participants with well-preserved pulmonary function taking elexacaftor + tezacaftor + ivacaftor (ETI) who discontinued dornase alfa or hypertonic saline for 6 weeks had no clinically meaningful decline in lung function. This may prompt discussions with care providers regarding ongoing use of these medications. OBJECTIVE: To compare the costs of outpatient medications between people taking ETI who continued or discontinued (1) dornase alfa or (2) hypertonic saline from 2 clinical trials and project cost differences in the US CF population if these 2 medications were used only intermittently for symptom relief instead of chronically. METHODS: The SIMPLIFY study was 2 parallel multicenter trials that randomized participants 1:1 to either continue or discontinue therapy. To estimate costs, we used data from the Merative MarketScan Databases to identify people with CF from 2020 to 2021. Our primary outcomes were differences in costs of outpatient prescription drugs among those who continued vs discontinued dornase alfa and, separately, hypertonic saline. We obtained adjusted differences in median costs. To estimate the annual cost savings if the population of people with CF taking ETI used these medications only intermittently, we multiplied the proportion of people in MarketScan with CF diagnoses who were taking each of these medications by the median cost savings per year and subtracted the cost of "rescue" use. RESULTS: A total of 392 participants from the dornase alfa trial and 273 from the hypertonic saline trial were included in analyses. The adjusted difference in median medication costs was not significant for the hypertonic saline trial, but we observed a significantly decreased 6-week cost of medications in the dornase alfa trial (adjusted median difference in costs between discontinue and continue of $5,860 (95% CI = $4,870-$6,850); P < 0.0001). We estimated that two-thirds of people with CF use ETI and dornase alfa in the United States; if they discontinued dornase alfa except for intermittent use, the resulting annual savings would be $1.21 billion. CONCLUSIONS: Although the costs of dornase alfa and hypertonic saline are smaller compared with ETI, reduction in use would lead to substantial prescription drug cost savings and reduce the treatment burden. However, individual benefits of these therapies should be considered, and decisions regarding changes in therapy remain an important discussion between people with CF and their providers. Study registration number: NCT04378153.


Assuntos
Fibrose Cística , Medicamentos sob Prescrição , Humanos , Fibrose Cística/tratamento farmacológico , Administração por Inalação , Medicamentos sob Prescrição/uso terapêutico , Coleta de Dados , Bases de Dados Factuais , Proteínas Recombinantes
2.
Am J Respir Crit Care Med ; 205(5): 529-539, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34784492

RESUMO

Rationale: The cystic fibrosis (CF) modulator drug, elexacaftor/tezacaftor/ivacaftor (ETI), proved highly effective in controlled clinical trials for individuals with at least one F508del allele, which occurs in at least 85% of people with CF. Objectives: PROMISE is a postapproval study to understand the broad effects of ETI through 30 months' clinical use in a more diverse U.S. patient population with planned analyses after 6 months. Methods: Prospective, observational study in 487 people with CF age 12 years or older with at least one F508del allele starting ETI for the first time. Assessments occurred before and 1, 3, and 6 months into ETI therapy. Outcomes included change in percent predicted FEV1 (ppFEV1), sweat chloride concentration, body mass index (BMI), and self-reported respiratory symptoms. Measurements and Main Results: Average age was 25.1 years, and 44.1% entered the study using tezacaftor/ivacaftor or lumacaftor/ivacaftor, whereas 6.7% were using ivacaftor, consistent with F508del homozygosity and G551D allele, respectively. At 6 months into ETI therapy, ppFEV1 improved 9.76 percentage points (95% confidence interval [CI], 8.76 to 10.76) from baseline, cystic fibrosis questionnaire-revised respiratory domain score improved 20.4 points (95% CI, 18.3 to 22.5), and sweat chloride decreased -41.7 mmol/L (95% CI, -43.8 to -39.6). BMI also significantly increased. Changes were larger in those naive to modulators but substantial in all groups, including those treated with ivacaftor at baseline. Conclusions: ETI by clinical prescription provided large improvements in lung function, respiratory symptoms, and BMI in a diverse population naive to modulator drug therapy, using existing two-drug combinations, or using ivacaftor alone. Each group also experienced significant reductions in sweat chloride concentration, which correlated with improved ppFEV1 in the overall study population. Clinical trial registered with www.clinicaltrials.gov (NCT NCT04038047).


Assuntos
Fibrose Cística , Adulto , Aminofenóis/uso terapêutico , Benzodioxóis/uso terapêutico , Criança , Agonistas dos Canais de Cloreto/uso terapêutico , Cloretos/análise , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística , Combinação de Medicamentos , Humanos , Indóis , Mutação , Estudos Prospectivos , Pirazóis , Piridinas , Pirrolidinas , Quinolonas , Resultado do Tratamento
3.
J Cyst Fibros ; 20(2): e16-e18, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33246911

RESUMO

Chronic Azithromycin (AZM) is a common treatment for lung infection. Among adults at risk of cardiac events, AZM use has been associated with cardiovascular harm. We assessed cardiovascular safety of AZM among children with CF, as a secondary analysis of a placebo-controlled, clinical trial, in which study drug was taken thrice-weekly for a planned 18 months. Safety assessments using electrocardiogram (ECG) occurred at study enrollment, and then after 3 weeks and 18 months of participation. Among 221 study participants with a median of 18 months follow-up, increased corrected QT interval (QTc) of ≥30 msec was rare, at 3.4 occurrences per 100 person-years; and incidence of QTc prolongation was no higher in the AZM arm than the placebo arm (1.8 versus 5.4 per 100 person-years). No persons experienced QTc intervals above 500 msec. Long-term chronic AZM use was not associated with increased QT prolongation.


Assuntos
Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Infecções por Pseudomonas/tratamento farmacológico , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/microbiologia , Adolescente , Antibacterianos/efeitos adversos , Azitromicina/efeitos adversos , Criança , Fibrose Cística/complicações , Método Duplo-Cego , Feminino , Humanos , Síndrome do QT Longo/induzido quimicamente , Masculino , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
J Pediatr Gastroenterol Nutr ; 71(6): 771-777, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32960827

RESUMO

OBJECTIVES: The nutritional status of children with cystic fibrosis (CF) is associated with mortality and morbidity. Intestinal inflammation may contribute to impaired digestion, absorption, and nutrient utilization in patients with CF and oral glutathione may reduce inflammation, promoting improved nutritional status in patients with CF. METHODS: The GROW study was a prospective, multicenter, randomized, placebo-controlled, double-blind, phase II clinical trial in pancreatic insufficient patients with CF between the ages of 2 and 10 years. Patients received reduced glutathione or placebo orally daily for 24 weeks. The primary endpoint was the difference in change in weight-for-age z-scores from baseline through week 24 between treatment groups. Secondary endpoints included other anthropometrics, serum, and fecal inflammatory markers in addition to other clinical outcomes. RESULTS: Fifty-eight participants completed the study. No significant differences were seen between glutathione (n = 30) and placebo (n = 28) groups in the 6-month change in weight-for-age z-score (-0.08; 95% CI: -0.22 to 0.06; P = 0.25); absolute change in weight (kg) (-0.18; 95% CI: -0.55 to 0.20; P = 0.35); or absolute change in BMI kg/m (-0.06; 95% CI: -0.37 to 0.25; P = 0.69). There were no significant differences in other secondary endpoints. Overall, glutathione was safe and well tolerated. CONCLUSIONS: Oral glutathione supplementation did not impact growth or change serum or fecal inflammatory markers in pancreatic insufficient children with CF when compared with placebo.


Assuntos
Fibrose Cística , Insuficiência Pancreática Exócrina , Glutationa , Criança , Pré-Escolar , Fibrose Cística/tratamento farmacológico , Método Duplo-Cego , Insuficiência Pancreática Exócrina/tratamento farmacológico , Insuficiência Pancreática Exócrina/etiologia , Glutationa/administração & dosagem , Humanos , Estudos Prospectivos
5.
Pediatr Pulmonol ; 54(5): 581-586, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30672141

RESUMO

IMPORTANCE: Treatment recommendations for infants with CF standardize care, but most surveillance or treatment guidance of pulmonary manifestations are consensus-based due to sparse evidence. OBJECTIVE: To report observations about pulmonary correlates of growth and other clinical features in infants with CF. METHODS: We analyzed data from the prospective Baby Observational and Nutrition Study conducted in 28 centers across the US, including clinical features, medications, guardian diaries of respiratory symptoms, oropharyngeal swab cultures and chest radiographs (CXR) collected over the first year of life. RESULTS: Cough was reported in 84% of infants in the first year. Up to 30% had clinically important cough but only 6.3% had crackles; 16.5% had wheeze. Wisconsin CXR score was above 5 in 23% (normal = 0; maximum score = 100). Pseudomonas was recovered from at least one respiratory culture in 24% of infants and was associated with crackles/wheezes and use of proton pump inhibitors (PPI) (OR = 5.47; 95%CI = 1.36, 21.92; P = 0.02) or PPI plus histamine-2 (H2) blocker (OR = 8.2; 95%CI = 2.41, 27.93; P = 0.001), but not H2 blocker alone. Hospitalization for respiratory indications occurred in 18% of infants and was associated with crackles/wheeze and abnormal CXR but not low weight, Pseudomonas or use of acid blockade. CONCLUSIONS: Cough is common in infants with CF, but few present with crackles/wheeze or CXR changes. Pseudomonas is associated with use of PPI or PPI plus H2 blocker, but not with respiratory hospitalization. These observations cannot prove cause and effect but add to our understanding of pulmonary manifestations of CF in infants. TRIAL REGISTRATION: United States ClinicalTrials.Gov registry NCT01424696 (clinicaltrials.gov).


Assuntos
Fibrose Cística/fisiopatologia , Estudos de Coortes , Tosse/epidemiologia , Fibrose Cística/diagnóstico por imagem , Fibrose Cística/epidemiologia , Feminino , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Estado Nutricional , Estudos Prospectivos , Inibidores da Bomba de Prótons/uso terapêutico , Infecções por Pseudomonas/epidemiologia , Sons Respiratórios , Infecções Respiratórias/epidemiologia , Estados Unidos/epidemiologia
6.
Am J Respir Crit Care Med ; 198(9): 1177-1187, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29890086

RESUMO

RATIONALE: New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence. OBJECTIVES: To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence. METHODS: The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF, 6 months to 18 years of age, with early Pa. Azithromycin or placebo was given 3× weekly with standardized TIS. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the time to pulmonary exacerbation requiring antibiotics and the secondary endpoint was the time to Pa recurrence, in addition to other clinical and safety outcomes. A total of 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the NHLBI because the trial had reached the prespecified interim boundary for efficacy. The risk of pulmonary exacerbation was reduced by 44% in the azithromycin group as compared with the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.37-0.83; P = 0.004). Weight increased by 1.27 kg in the azithromycin group compared with the placebo group (95% confidence interval, 0.01-2.52; P = 0.046). No significant differences were seen in microbiological or other clinical or safety endpoints. CONCLUSIONS: Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa. Clinical trial registered with clinicaltrials.gov (NCT02054156).


Assuntos
Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Fibrose Cística/complicações , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/tratamento farmacológico , Administração por Inalação , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Quimioterapia Combinada/métodos , Feminino , Humanos , Lactente , Masculino , Pseudomonas aeruginosa/efeitos dos fármacos , Recidiva , Fatores de Tempo , Tobramicina/administração & dosagem , Tobramicina/uso terapêutico , Resultado do Tratamento
7.
J Pediatr Gastroenterol Nutr ; 66(4): 657-663, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29176494

RESUMO

OBJECTIVES: The aim of the study is to describe pancreatic enzyme practices during the first year of life in infants with cystic fibrosis (CF) and evaluate associations between dosing and outcomes, including growth and gastrointestinal (GI) symptoms. METHODS: We analyzed data from a subset of infants who were in a prospective cohort study conducted at 28 US CF centers. Anthropometric measurements and medications were recorded at each visit. Diaries with infant diet, pancreatic enzyme replacement therapy (PERT) dosing, stool frequency and consistency, and pain were completed by a parent/guardian for 3 days before each visit. RESULTS: Two hundred and thirty-one infants were enrolled in the main study; 205 of these met criteria for pancreatic insufficiency (PI). PERT dose between birth and 6 months was on average 1882 LU/kg per meal (range: 492-3727) and was similar between 6 and 12 months (mean: 1842 LU/kg per mean, range: 313-3612). PERT dose had a weak, negative association with weight z score at 3 and 6 months (r = -0.16, 95% confidence interval [CI] -0.29 to -0.02 and r = -0.18, 95% CI -0.31 to -0.04, respectively) but not at 12 months. There was not a clear relationship between PERT dosing and number of stools per day, stool consistency or pain. One hundred and forty-four infants (70%) were placed on acid suppression medication. Weight z score mean was 0.37 higher in infants using proton pump inhibitors (PPIs) exclusively versus those using histamine-2 blockers exclusively (95% CI -0.02 to 0.76, P = 0.06). CONCLUSIONS: We did not observe that centers with a higher PERT dosing strategy yielded greater clinical benefit than dosing at the lower end of the recommended range.


Assuntos
Fibrose Cística/terapia , Terapia de Reposição de Enzimas/métodos , Insuficiência Pancreática Exócrina/terapia , Antropometria , Desenvolvimento Infantil/efeitos dos fármacos , Estudos de Coortes , Fibrose Cística/complicações , Relação Dose-Resposta a Droga , Insuficiência Pancreática Exócrina/etiologia , Humanos , Lactente , Recém-Nascido , Triagem Neonatal/métodos , Estudos Prospectivos , Resultado do Tratamento , Estados Unidos
8.
JAMA Pediatr ; 171(6): 546-554, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28437538

RESUMO

Importance: Since the implementation of universal newborn screening (NBS) for cystic fibrosis (CF), the timing and magnitude of growth deficiency or its association with correlates of disease among infants with CF who underwent NBS has not been well described. Objective: To examine incremental weight gain, linear growth, and clinical features in the first year of life among infants with CF who underwent NBS. Design, Setting, and Participants: The Baby Observational and Nutrition Study (BONUS), a multicenter, longitudinal, observational cohort study, was conducted during regular CF clinic visits in the first 12 months of life at 28 US Cystic Fibrosis Foundation-accredited Care Centers from January 7, 2012, through May 31, 2015. Participants included 231 infants younger than 3.5 months who underwent NBS and had confirmed CF, with a gestational age of at least 35 weeks, birth weight of at least 2.5 kg, and toleration of full oral feeds. Of these, 222 infants (96.1%) had follow-up beyond 6 months of age and 215 (93.1%) completed 12 months of follow-up. Exposure: Cystic fibrosis. Main Outcome and Measures: Attained weight and length for age and World Health Organization normative z scores at ages 1 to 6 and 8, 10, and 12 months (defined a priori). Results: Of the 231 infants enrolled, 110 infants (47.6%) were female and 121 (52.4%) were male, with a mean (SD) age of 2.58 (0.69) months. BONUS infants had lower than mean birth weights (mean z score, -0.15; 95% CI, -0.27 to -0.04) and higher birth lengths (mean z score, 0.44; 95% CI, 0.26 to 0.62). They achieved normal weight by 12 months, a significant improvement over a prescreening cohort of newborns with CF from 20 years before the contemporary cohort (mean z score increase, 0.57; 95% CI, 0.37-0.77). However, length was lower than the mean at 12 months (mean z score, -0.56; 95% CI, -0.70 to -0.42). Only 30 infants (13.6%) were at less than the 10th percentile of weight for age, whereas 53 (23.9%) were at less than the 10th percentile of length for age at more than half their visits. Male sex, pancreatic insufficiency, meconium ileus, histamine blocker use, and respiratory Pseudomonas aeruginosa infection were associated with lower weight or length during the first year. Insulinlike growth factor 1 levels were significantly lower among low-length infants. Persistently low-weight infants consumed significantly more calories, and weight and length z scores were negatively correlated with caloric intake. Conclusions and Relevance: Since initiation of universal NBS for CF, significant improvement has occurred in nutritional status, with normalization of weight in the first year of life. However, length stunting remains common.


Assuntos
Fibrose Cística/diagnóstico , Triagem Neonatal/métodos , Aumento de Peso/fisiologia , Antropometria/métodos , Peso ao Nascer/fisiologia , Estatura/fisiologia , Peso Corporal/fisiologia , Aleitamento Materno , Fibrose Cística/fisiopatologia , Seguimentos , Idade Gestacional , Crescimento/fisiologia , Humanos , Lactente , Fenômenos Fisiológicos da Nutrição do Lactente/fisiologia , Recém-Nascido , Estado Nutricional , Apoio Nutricional/métodos
9.
J Pediatric Infect Dis Soc ; 4(3): 225-31, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26336603

RESUMO

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) infects ∼25% of patients with cystic fibrosis (CF) in the United States. We hypothesized that health-related outcomes differed between healthcare-associated (staphylococcal cassette chromosome mec [SCCmec] II) vs community-associated (SCCmec IV) MRSA strains in patients chronically infected with CF. METHODS: At 7 CF centers, MRSA isolates were prospectively obtained from patients ≤18 years old with 2 or more positive MRSA cultures within 1 year. Isolates were classified by SCCmec type and Panton-Valentine-leukocidin (PVL) status at a core laboratory, and sites remained blinded to SCCmec type and PVL results. Prospective clinical data including antibiotic use, respiratory symptoms, and pulmonary exacerbations were obtained. RESULTS: Among the 295 cohort participants with typeable MRSA isolates, 69.5% had SCCmec II PVL(-), 13.2% had SCCmec IV PVL(-), and 17.3% had SCCmec IV PVL(+) strains. During follow-up of 287 patients with prospective data after enrollment, the risk for pulmonary exacerbations was significantly higher among participants with SCCmec II than SCCmec IV strains (risk ratio [RR] = 1.13; P = .03) and higher in those with SCCmec IV PVL(-) than SCCmec IV PVL(+) strains (RR = 1.62; P < .0001). Neither decline in lung function nor changes in nutritional outcomes differed by SCCmec type or PVL status during the study period. CONCLUSIONS: Participants harboring chronic SCCmec II MRSA received more antibiotics and may have more lung disease than those with SCCmec IV; PVL(+) isolates were not associated with more advanced disease.


Assuntos
Antibacterianos/administração & dosagem , Fibrose Cística/complicações , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/tratamento farmacológico , Adolescente , Antibacterianos/efeitos adversos , Toxinas Bacterianas , Criança , Pré-Escolar , Doença Crônica , Fibrose Cística/tratamento farmacológico , Exotoxinas , Feminino , Humanos , Leucocidinas , Masculino , Staphylococcus aureus Resistente à Meticilina/classificação , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/etiologia , Resultado do Tratamento , Estados Unidos
10.
Clin Infect Dis ; 61(5): 707-15, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25972024

RESUMO

BACKGROUND: Pseudomonas aeruginosa (Pa) is the most important pathogen infecting the airways in individuals with cystic fibrosis. A key question is whether children with newly acquired Pa infection who are able to achieve sustained eradication after early antipseudomonal therapy demonstrate improved long-term health outcomes compared with those who are unable to achieve a sustained microbiologic response. METHODS: This cohort study utilized observational follow-up data on children participating in the Early Pseudomonas Infection Control trial who received standardized therapy for newly acquired Pa. Sustained eradicators were defined as those who maintained Pa-negative cultures for 12 months after initial antipseudomonal therapy. Associations between eradication status and outcomes were assessed. RESULTS: Of the 249 trial participants included in the study, 172 (69%) achieved sustained eradication of Pa during the trial (sustained eradicators). Over the median 5-year follow-up, sustained eradicators had a 74% reduced risk of developing chronic Pa (hazard ratio [HR], 0.26; 95% confidence interval [CI], .17-.40) and a 57% reduced risk of mucoidy (HR, 0.43; 95% CI, .25-.73) compared with nonsustained eradicators. Sustained eradicators had significantly less anti-Pa antibiotic usage during follow-up compared with nonsustained eradicators. There was no association between eradication status and clinical outcomes including rate of exacerbation and lung function decline. CONCLUSIONS: This is the first study to quantify the long-term durability of microbiological response associated with early antipseudomonal therapy, demonstrating the critical importance of optimizing antipseudomonal therapies during early Pa infection. The clinical impact of failure to achieve sustained Pa eradication remains unclear, however, and may be confounded by anti-Pa antibiotic usage. CLINICAL TRIALS REGISTRATION: NCT00097773.


Assuntos
Antibacterianos/uso terapêutico , Fibrose Cística/epidemiologia , Fibrose Cística/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/epidemiologia , Pseudomonas aeruginosa , Antibacterianos/administração & dosagem , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Lactente , Masculino , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/fisiopatologia , Resultado do Tratamento
11.
Ann Am Thorac Soc ; 12(6): 864-71, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25745825

RESUMO

RATIONALE: Methicillin-resistant Staphylococcus aureus (MRSA) prevalence continues to increase in patients with cystic fibrosis (CF) in the United States, reaching 26.5% in 2012. Approximately 30% of strains are SCCmec (staphylococcal cassette chromosome mec) IV type, frequently USA300, which in the general population have different genotypic and phenotypic features than SCCmec II type. OBJECTIVES: We hypothesized that risk factors for acquisition and outcomes in patients with CF differed for "health care-associated" (SCCmec II) versus "community-associated" (SCCmec IV) MRSA strains. METHODS: To determine the role of SCCmec type and Panton-Valentine leukocidin (PVL), MRSA isolates from patients not more than 18 years old at seven CF centers were typed and the association of potential risk factors and subsequent clinical course was assessed, using data provided by the CF Patient Registry. MEASUREMENTS AND MAIN RESULTS: Participants with chronic MRSA (295) had typeable isolates and clinical data; 205 (69.5%) had SCCmec II PVL(-), 39 (13.2%) had SCCmec IV PVL(-), and 51 (17.3%) had SCCmec IV PVL(+) strains. SCCmec IV, compared with SCCmec II, increased during the study period, 1996-2010 (P = 0.03). SCCmec II was associated with Pseudomonas aeruginosa-positive cultures and three or more clinic visits in the 6 months preceding the first positive MRSA culture (adjusted odds ratio, 2.05; 95% confidence interval, 1.13-3.74; P = 0.019). Lung function and anthropometrics remained unchanged in the 6 months after initial MRSA detection compared with the 6 months prior. Although CF care increased for participants in both groups in the 6 months after MRSA detection, inhaled antibiotics were prescribed more frequently in those with SCCmec II strains and increased hospitalizations occurred in those with SCCmec IV PVL(-) strains compared with those with PVL(+) strains (adjusted difference, 34.10%; 95% confidence interval, 7.58-60.61; P = 0.012). Participants in both groups had an increase in CF care in the 2 years after MRSA detection compared with the 2 years prior. CONCLUSIONS: Increased exposure to CF clinics and P. aeruginosa may constitute risk factors for acquisition of SCCmec II MRSA strains. Clinical interventions increased 6 months and 2 years after initial MRSA detection regardless of SCCmec type.


Assuntos
Antibacterianos/uso terapêutico , Fibrose Cística , Staphylococcus aureus Resistente à Meticilina , Pseudomonas aeruginosa/isolamento & purificação , Infecções Estafilocócicas , Adolescente , Toxinas Bacterianas/análise , Criança , Pré-Escolar , Coinfecção , Fibrose Cística/complicações , Fibrose Cística/diagnóstico , Fibrose Cística/epidemiologia , Fibrose Cística/microbiologia , DNA Bacteriano/análise , Exotoxinas/análise , Feminino , Técnicas de Genotipagem , Humanos , Leucocidinas/análise , Masculino , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/diagnóstico , Sistema de Registros , Testes de Função Respiratória , Fatores de Risco , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/etiologia , Estados Unidos/epidemiologia , Fatores de Virulência/análise
12.
J Cyst Fibros ; 13(1): 74-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24029220

RESUMO

BACKGROUND: Current definitions of pulmonary exacerbation (PE) in cystic fibrosis are based on studies in participants with significant lung disease and may not reflect the spectrum of findings observed in younger patients with early lung disease. METHODS: We used data from a recent trial assessing the efficacy of azithromycin in children to study signs and symptoms associated with PEs and related changes in lung function and weight. RESULTS: While increased cough was present in all PEs, acute weight loss and reduction in oxygen saturation were not observed. Changes in lung function did not differ between subjects who did experience a PE and those who were exacerbation-free. CONCLUSIONS: Cough was the predominant symptom in CF patients with early lung disease experiencing a PE. There was no significant difference in mean 6-month change in lung function or weight among subjects with one or more exacerbations and those without an exacerbation.


Assuntos
Azitromicina/uso terapêutico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/fisiopatologia , Pneumopatias/tratamento farmacológico , Pneumopatias/fisiopatologia , Adolescente , Adulto , Antibacterianos/uso terapêutico , Criança , Tosse/tratamento farmacológico , Tosse/fisiopatologia , Fibrose Cística/patologia , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Pulmão/patologia , Pulmão/fisiopatologia , Pneumopatias/patologia , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/patologia , Infecções Respiratórias/fisiopatologia
13.
Contemp Clin Trials ; 36(1): 99-105, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23770109

RESUMO

BACKGROUND: In a chronic disease setting such as cystic fibrosis (CF), antibiotics are often prescribed for emergent symptoms and it is unclear whether this affects endpoints in a clinical trial. Pulmonary exacerbations (PEs) are defined episodes of acute worsening and a key clinical efficacy measure in CF. Our hypothesis was that acute antibiotics given for illnesses not meeting the PE definition may alter estimates of treatment effect that do not account for this antibiotic use. METHODS: A randomized, placebo-controlled trial of azithromycin (AZ) including 260 participants with CF was utilized for this study. PEs were defined using a priori criteria. Physician initiated antibiotic therapy (PIT) not meeting the PE endpoint was characterized and its impact on treatment effect assessed. RESULTS: 40% (104/260) of participants were prescribed 188 courses of PIT in the absence of a PE; 19% (25/129) of placebo and 10% (13/131) of AZ participants received ≥2 courses of PIT and never fulfilled the PE definition (9% difference, 95% confidence interval: 1%, 18%, p = 0.04). Accounting for PIT through use of a composite endpoint including time to PE or need for repeated PIT altered treatment effect estimates (a 56% reduction in the event rate comparing AZ to placebo [p < 0.0001] as compared to a 50% reduction not accounting for PIT [p = 0.003]). CONCLUSION: PIT is common in CF and may impact treatment effect estimates. Optimization of the PE endpoint to include meaningful events necessitating treatment may improve our ability to conduct efficient trials by reducing the sample size 30-50%, ultimately enabling rapid evaluation of new therapies.


Assuntos
Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Protocolos Clínicos , Fibrose Cística/complicações , Pneumopatias/tratamento farmacológico , Pneumopatias/etiologia , Adolescente , Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Criança , Feminino , Humanos , Masculino , Projetos de Pesquisa , Tamanho da Amostra
14.
Eur Respir J ; 42(6): 1545-52, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23722613

RESUMO

The optimal strategy for monitoring cystic fibrosis lung disease in infancy remains unclear. Our objective was to describe longitudinal associations between infant pulmonary function tests, chest radiograph scores and other characteristics. Cystic fibrosis patients aged ≤24 months were enrolled in a 10-centre study evaluating infant pulmonary function tests four times over a year. Chest radiographs ∼1 year apart were scored using the Wisconsin and Brasfield systems. Associations of infant pulmonary function tests with clinical characteristics were evaluated with mixed effects models. The 100 participants contributed 246 acceptable flow/volume (forced expiratory volume in 0.5 s (FEV0.5) and forced expiratory flow at 75% of the forced vital capacity (FEF75%)), 303 functional residual capacity measurements and 171 chest radiographs. Both Brasfield and Wisconsin chest radiograph scores worsened significantly over the 1-year interval. Worse Wisconsin chest radiograph scores and Staphylococcus aureus were both associated with hyperinflation (significantly increased functional residual capacity), but not with diminished FEV0.5 or FEF75%. Parent-reported cough was associated with significantly diminished forced expiratory flow at 75% but not with hyperinflation. In this infant cohort in whom we previously reported worsening in average lung function, chest radiograph scores also worsened over a year. The significant associations detected between both Wisconsin chest radiograph score and S. aureus and hyperinflation, as well as between cough and diminished flows, reinforce the ability of infant pulmonary function tests and chest radiographs to detect early cystic fibrosis lung disease.


Assuntos
Fibrose Cística/diagnóstico por imagem , Fibrose Cística/fisiopatologia , Pulmão/fisiopatologia , Tosse , Fibrose Cística/complicações , Feminino , Volume Expiratório Forçado , Capacidade Residual Funcional , Humanos , Lactente , Estudos Longitudinais , Pulmão/diagnóstico por imagem , Pulmão/microbiologia , Masculino , Radiografia Torácica , Reprodutibilidade dos Testes , Testes de Função Respiratória , Infecções Estafilocócicas/diagnóstico , Staphylococcus aureus , Estados Unidos
15.
Contemp Clin Trials ; 34(2): 232-8, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23200843

RESUMO

RATIONALE: Emergence of elevated liver function tests (LFTs) during a clinical trial may be due to underlying disease factors of the participants, thus cofounding safety assessments of therapies. Limited data exist addressing the frequency of elevated LFTs in the chronic disease setting of cystic fibrosis (CF). The objectives of this study were to characterize emergence rates of elevated LFTs in CF trials and their association with clinical outcomes. METHODS: The cohort was comprised of participants of three completed multicenter CF trials. LFTs were collected as safety endpoints, and hospitalization rates and changes in pulmonary function and weight were used to assess the association between elevated LFTs and clinical outcome. RESULTS: 93/376 (25%) participants had ≥1 emergent elevated LFT exceeding the normal reference range over an average 8.3 month follow-up, and only 12/93 (13%) had a value determined by the physician as clinically significant. The emergence of an elevated LFT was not significantly associated with a greater rate of decline in pulmonary function or weight as compared to participants with normal LFTs. The emergence of an elevated LFT value was however associated with a higher hospitalization risk (relative risk:1.67, 95% confidence interval:1.11, 2.53). CONCLUSIONS: Elevated LFTs are common among CF trials, although in most cases they are not deemed clinically significant. These elevated LFTs are associated with more frequent hospitalizations, but additional studies are needed to determine the causality of this association. Therapeutic trials in CF must define a priori criteria for clinical significance of elevated LFTs to enable unbiased safety assessments.


Assuntos
Alanina Transaminase/efeitos dos fármacos , Antibacterianos/efeitos adversos , Aspartato Aminotransferases/efeitos dos fármacos , Fibrose Cística/sangue , Infecções por Pseudomonas/tratamento farmacológico , gama-Glutamiltransferase/efeitos dos fármacos , Adolescente , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores Farmacológicos/sangue , Criança , Pré-Escolar , Estudos de Coortes , Fibrose Cística/complicações , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Testes de Função Hepática , Masculino , Infecções por Pseudomonas/complicações , Testes de Função Respiratória , Adulto Jovem , gama-Glutamiltransferase/sangue
16.
Eur Respir J ; 41(1): 60-6, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22653767

RESUMO

This study aimed to describe lung function in a cohort of children with cystic fibrosis (CF) who underwent infant pulmonary function tests (IPFTs) and preschool spirometry. Children performed up to four IPFTs (raised volume rapid thoracic compression technique) over 1 yr and five preschool spirometry tests over up to 2 yrs during participation in prospective, multicentre studies of infant and preschool lung function. All lung function data were reviewed centrally for measurement acceptability. 45 children had 252 acceptable measurements (137 IPFTs and 115 preschool spirometries) at ages 0.3-6.5 yrs. The median number of measurements per participant was 6 (range 3-9). Recent Pseudomonas aeruginosa infection was associated with 5.1% (95% CI 0.01-9.9%) lower forced expiratory volume in 0.5 s (FEV(0.5)) and 16.4% (95% CI 7.0-24.9%) lower forced expiratory flow at 25-25% of forced vital capacity (FEF(25-75%)), after adjustment for length, test type and centre. Recent cough was associated with 5.7% (95% CI 1.1-10.1%) lower FEV(0.5) and 10.1% (95% CI 0.6-18.7%) lower FEF(25-75%). Even after accounting for infection status, cough, sex, length, test type and centre, there was significant inter-individual variability in lung function (p<0.01 for each of FEV(0.5), FEF(25-75%) and forced vital capacity). Recent P. aeruginosa infection and cough are associated with lower lung function in children with CF. Significant inter-individual variability in lung function remains to be explained.


Assuntos
Fibrose Cística/fisiopatologia , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Prospectivos , Testes de Função Respiratória
17.
Pediatr Pulmonol ; 47(7): 641-8, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22684984

RESUMO

BACKGROUND: We previously performed a randomized placebo-controlled trial to examine the effects of azithromycin in children and adolescents 6-18 years of age with cystic fibrosis uninfected with Pseudomononas aeruginosa and demonstrated that while azithromycin did not acutely improve pulmonary function, azithromycin-reduced pulmonary exacerbations, decreased the initiation of new oral antibiotics, and improved weight gain. We now report the results of the open-label, follow-on study to assess durability of response to azithromycin and continued safety and tolerability. METHODS: Eligible participants were enrolled in a 24-week open-label study of azithromycin to compare efficacy and safety endpoints during the placebo-controlled trial versus open-label study in two groups: participants initially on azithromycin continued azithromycin (azithromycin-azithromycin) and participants initially on placebo who then received azithromycin (placebo-azithromycin). As in the placebo-controlled trial, the azithromycin dose in the open-label study was 250 mg Monday-Wednesday-Friday for participants weighing 18-35.9 kg and 500 mg Monday-Wednesday-Friday for participants weighing 36 kg or greater. RESULTS: Of 174 eligible participants, 146 (83.9%) enrolled in the open-label study. No significant improvements in lung function were observed within either group. There were no differences in outcomes in the placebo-azithromycin group during the placebo-controlled versus open-label phase. The azithromycin-azithromycin group had comparable odds of experiencing an exacerbation during the two phases (OR 1.6, CI(95) 0.8, 3.0) and stable weight gain, but new oral antibiotics were initiated more frequently during the open-label study (OR 1.9, CI(95) 1.0, 3.5). In both groups, adverse event rates were comparable during the placebo-controlled and open-label study and treatment-emergent pathogens were rare. CONCLUSIONS: During the open-label study, we observed continued durability of treatment response to azithromycin, as measured by pulmonary exacerbations and continued weight gain, although use of oral antibiotics increased. There were no new safety concerns. Currently available data suggest that azithromycin reduces exacerbations and improves weight gain for 6-12 months among children and adolescents with CF uninfected with P. aeruginosa.


Assuntos
Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Fibrose Cística/tratamento farmacológico , Adolescente , Antibacterianos/efeitos adversos , Azitromicina/efeitos adversos , Criança , Fibrose Cística/fisiopatologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Masculino , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Testes de Função Respiratória , Resultado do Tratamento , Aumento de Peso/efeitos dos fármacos
18.
Chest ; 142(5): 1259-1266, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22595153

RESUMO

BACKGROUND: While the mechanism of action by which azithromycin exerts positive effects inpatients with cystic fibrosis remains unclear, evidence suggests that azithromycin may act as an immunomodulatory agent. We examined changes in systemic inflammatory markers in a doubleblind, randomized, controlled trial of oral azithromycin in patients 6-18 years of age with cystic fibrosis who were uninfected with Pseudomonas aeruginosa. METHODS: WBC counts and differential, serum myeloperoxidase (MPO), high-sensitivity C reactive protein (hsCRP), intracellular adhesion molecule 1, IL-6, calprotectin, serum amyloid A (SAA),and granulocyte colony-stimulating factor (G-CSF) were measured at baseline and after 28 and 168 days of treatment in patients receiving either oral azithromycin or placebo. RESULTS: Inflammatory markers were similar in both groups at baseline. HsCRP, MPO, SAA, calprotectin,and the absolute neutrophil count (ANC) significantly decreased from baseline today 28 in the azithromycin group compared with the placebo group ( P < .05). This treatment effect was sustained at day 168 for ANC, calprotectin, and SAA ( P < .05). Changes in hsCRP, calprotectin,and SAA at day 28 were negatively correlated with changes in FEV 1 (L) and FEV 1(% predicted), as well as both absolute and relative changes in weight ( P < .05). Except for weight (%),the associations remained significant for calprotectin; FEV 1 (L) and weight (%) remained significantly correlated with the 168-day change in hsCRP. The 168-day change in ANC was significantly correlated with changes in lung function, but not in weight; the change in G-CSF was significantly correlated with the change in weight (%) only. CONCLUSIONS: In patients not infected with P aeruginosa , oral azithromycin significantly reduced neutrophil counts and serum inflammatory markers within 28 days of initiating treatment. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00431964; URL: www.clinicaltrials.gov


Assuntos
Azitromicina/uso terapêutico , Biomarcadores/sangue , Fibrose Cística/tratamento farmacológico , Adolescente , Azitromicina/administração & dosagem , Proteína C-Reativa/metabolismo , Criança , Fibrose Cística/fisiopatologia , Método Duplo-Cego , Feminino , Fator Estimulador de Colônias de Granulócitos/sangue , Humanos , Molécula 1 de Adesão Intercelular/sangue , Interleucina-6/sangue , Contagem de Leucócitos , Complexo Antígeno L1 Leucocitário/sangue , Masculino , Peroxidase/sangue , Placebos , Pseudomonas aeruginosa/isolamento & purificação , Testes de Função Respiratória , Proteína Amiloide A Sérica/metabolismo , Resultado do Tratamento
19.
Pediatr Pulmonol ; 47(6): 597-605, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22081559

RESUMO

RATIONALE: Conducting clinical trials in cystic fibrosis (CF) preschoolers has been limited by lack of sensitive lung function measures performed across sites. OBJECTIVES: (1) Assess feasibility and short-term reproducibility of spirometry, forced oscillometry (FO), and inductance plethysmography (IP) in a multi-center preschool population; (2) compare ability of each technique to differentiate lung function of CF preschoolers and controls; (3) evaluate longitudinal changes in lung function; (4) estimate sample sizes for future trials. METHODS: A longitudinal, multi-center study of CF preschoolers was conducted utilizing standardized equipment, rigorous site training, and centralized lung function data review. CF subjects participated in up to four study visits 6 months apart, plus a 2-week reproducibility visit. Controls had one study visit. RESULTS: Ninety-three CF subjects and 87 controls participated. Acceptability rates were lowest for spirometry (55%) and highest for IP (77%). Spirometry success increased with age and having a prior acceptable measurement. FEV(1) , FEV(0.5) , and FEF(25-75) were lower for CF subjects than for controls; spirometric z-scores declined with age. IP measures of thoracoabdominal asynchrony were greater for CF subjects than for controls. FO indices did not distinguish CF from controls. FEV(1) and FEV(0.5) are able to detect the smallest treatment effect for a given sample size. CONCLUSIONS: Spirometry appears more sensitive than IP or FO for detecting lung disease in CF preschoolers; spirometric indices decline with age. Future trials using spirometry should include a run-in period for training and require acceptable data prior to enrollment. However, near-normal spirometric measurements in CF preschoolers may lead to difficulty detecting a treatment effect.


Assuntos
Fibrose Cística/diagnóstico , Testes de Função Respiratória/normas , Estudos de Casos e Controles , Pré-Escolar , Ensaios Clínicos como Assunto/métodos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Oscilometria , Pletismografia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espirometria
20.
Pediatr Pulmonol ; 47(6): 574-81, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22081584

RESUMO

OBJECTIVE: To analyze cross-sectional and longitudinal associations between lung function measures and clinical features in a cohort of preschool children with cystic fibrosis (CF). METHODS: Longitudinal eight-center observational study of children with CF aged 36-60 months at enrollment, who underwent semiannual pulmonary function tests (PFTs) for up to 2 years consisting of spirometry (all 8 sites), forced oscillometry (FO, 5 sites), and measures of thoracoabdominal asynchrony using respiratory inductive plethysmography (IP, 5 sites). RESULTS: Ninety-three subjects were enrolled; 181 acceptable spirometry measurements from 71 subjects, 128 FO from 47 subjects, and 142 IP from 50 subjects were available for analysis. Cross sectional analyses did not detect an association between any PFT parameter at enrollment and Pseudomonas aeruginosa (Pa) status, CF gene mutation class, Wisconsin cough score, Shwachman score, environmental tobacco smoke exposure, family history of asthma, or nutritional indices. In longitudinal analyses, Pa infection within 6 months preceding enrollment was associated with a significantly greater rate of decline in z-scores for forced expiratory flow between 25 and 75% of forced vital capacity (FEF(25-75) ) (-1.3 vs. -0.4 Z scores/year, P = 0.024) and greater thoracoabdominal asynchrony measured by IP (mean phase angle difference 4.6°, P = 0.004). No other significant longitudinal associations were observed. CONCLUSIONS: Prior Pa infection is associated with a greater rate of decline in FEF(25-75) z-score and mild thoracoabdominal asynchrony in preschool children with CF. In this multicenter US study, significant associations between other lung function measures and clinical features were not detected.


Assuntos
Tosse/complicações , Fibrose Cística/complicações , Fibrose Cística/fisiopatologia , Infecções por Pseudomonas/complicações , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Estudos Longitudinais , Oscilometria , Pletismografia , Pseudomonas aeruginosa , Espirometria , Poluição por Fumaça de Tabaco
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