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Daniel J Wolter,
Julia C Emerson,
Sharon McNamara,
Anne M Buccat,
Xuan Qin,
Elizabeth Cochrane,
Laura S Houston,
Geraint B Rogers,
Peter Marsh,
Karandeep Prehar,
Christopher E Pope,
Marcella Blackledge,
Eric Déziel,
Kenneth D Bruce,
Bonnie W Ramsey, Ronald L Gibson,
Jane L Burns,
Lucas R Hoffman
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ABSTRACT: Background. Cystic fibrosis (CF) lung disease is associated with diverse bacteria chronically infecting the airways. Slow-growing, antibiotic-resistant mutants of Staphylococcus aureus known as small-colony variants (SCVs) have been isolated from respiratory secretions from European adults and children with CF lung disease using specific but infrequently-used culture techniques. S. aureus SCVs can be selected either by exposure to specific antibiotics or by growth with another CF pathogen, Pseudomonas aeruginosa. We sought to determine the prevalence, clinical significance, and likely mechanisms of selection of S. aureus SCVs among a US cohort of children with CF. Methods. We performed a two-year study of 100 children with CF using culture techniques sensitive for S. aureus SCVs, and evaluated associations with clinical characteristics using multivariable regression models. Results. S. aureus SCV infection was detected among 24% of participants and was significantly associated with a greater drop in lung function during the study (p=0.007, adjusted for age and lung function at enrollment). This association persisted after adjusting for infection with other known CF pathogens, including P. aeruginosa and methicillin-resistant S. aureus. Evidence indicated that S. aureus SCVs were likely selected in vivo by treatment with the antibiotic trimethoprim-sulfamethoxazole (TMP-SMX) and possibly by co-infection with P. aeruginosa. Conclusions. Infection with SCV S. aureus was independently associated with worse CF respiratory outcomes in this pediatric cohort. As many clinical microbiology laboratories do not specifically detect S. aureus SCVs, validation and extension of these findings would require widespread changes in the usual laboratory and clinical approach to these bacteria.
Clinical Infectious Diseases 04/2013; · 9.15 Impact Factor
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Michael Anstead,
Sonya L Heltshe,
Umer Khan,
Joseph T Barbieri,
Markus Langkamp,
Gerd Döring,
Shimoni Dharia, Ronald L Gibson,
Miriam M Treggiari,
James Lymp,
Margaret Rosenfeld,
Bonnie Ramsey
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ABSTRACT: BACKGROUND: The prognostic value of Pseudomonas aeruginosa serology for antibiotic therapy in cystic fibrosis patients is not well understood. METHODS: Using five antigens from two ELISAs, we assessed whether positive serology in CF patients participating in the multi-center Early Pseudomonas Infection in Children (EPIC) trial would predict treatment failure, time to pulmonary exacerbation and risk for recurrent P. aeruginosa isolation post eradication. RESULTS: Baseline positive P. aeruginosa serology was not significantly associated with failure of initial P. aeruginosa eradication measured at week 10 (adjusted for baseline culture) but seropositivity to the antigens alkaline protease and exotoxin A was significantly associated with increased risk for recurrent P. aeruginosa isolation during the 60week post eradication follow-up period (p=0.003 and p=0.001 respectively). There was no association between baseline seropositivity and time to pulmonary exacerbation. CONCLUSION: P. aeruginosa serology may complement culture results in clinicians' efforts to successfully monitor recurrence of early P. aeruginosa in CF patients.
Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society 08/2012; · 3.19 Impact Factor
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ABSTRACT: BACKGROUND: Risk factors for initial Pseudomonas aeruginosa (Pa) acquisition, particularly environmental exposures, are poorly understood. We aimed to identify such risk factors in order to inform prevention strategies and identify high-risk populations. METHODS: The study cohort included all participants in the U.S. EPIC Observational Study who had no prior Pa-positive respiratory cultures (N=889). Cox proportional hazard models were used to test the effects of factors on age at first Pa-positive respiratory culture. RESULTS: Cystic fibrosis (CF) genotype functional class had an important effect on age at initial Pa acquisition (hazard ratio (HR) comparing minimal to residual CFTR function 2.87 (95% CI 1.88, 4.39)). None of the modifiable risk factors evaluated, including cigarette smoke, hot tub use, breastfeeding, or daycare, was associated with age at Pa acquisition. Similarly, newborn screening was not associated with age at Pa acquisition (HR 0.85, 95% CI 0.66, 1.09). Key associations were validated in a CF Foundation National Patient Registry replication cohort. CONCLUSIONS: Given the ubiquitous presence of Pa in the environment, it may be that many imposed lifestyle changes will have less impact on age at initial Pa acquisition than genetic determinants.
Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society 05/2012; 11(5):446-453. · 3.19 Impact Factor
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ABSTRACT: Evaluation of physical activity is integral to the assessment of daily physical function and a potential objective outcome measure for clinical trials. We evaluated the feasibility of using pedometers to measure physical activity in adolescents and adults with cystic fibrosis (CF) and assessed the responsiveness of its measurement to changes in health state.
Participants were recruited through two CF clinics in Seattle, WA. Subjects were instructed to use their pedometer for at least one ill and two well periods (each lasting 7 days). Step rate was calculated as steps per hour of use. Daily symptoms were also recorded using the CF Respiratory Symptom Diary (CFRSD). Generalized estimating equation linear regression was used to compare mean step rate between health states and by self-reported symptom category.
We enrolled 30 CF patients with a mean (±SD) age of 22 (±7) years and a mean forced expiratory volume in 1s (FEV(1)) of 57% (±25%) predicted. The mean period step rate increased from 397 (95% CI 324-497) steps/hour when ill to 534 (95% CI 413-654) steps/hour when well (p=0.015). Pedometer-recorded step rate also correlated with self-reported physical activity items on the CFRSD.
Step rate measured with a pedometer correlates significantly with changes in health status and self-reported activity, and could be used as an outcome measure in CF.
Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society 01/2012; 11(3):216-22. · 3.19 Impact Factor
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ABSTRACT: Viral detection from different respiratory sample types in children with cystic fibrosis (CF) is facilitated by available molecular methods, but optimum sampling strategies have not been identified. In addition, associations between viral detection and respiratory symptoms are not well described.
Study goals were to compare molecular detection of viruses from concurrent upper airway and sputum samples in children with CF and to describe relative frequency of respiratory viral infections and identify potential clinical associations.
We conducted a 2-year prospective surveillance study in 44 children with CF aged 6-18 years. Upper airway and sputum samples were collected quarterly and during pulmonary exacerbations and tested for respiratory syncytial virus (RSV), influenza viruses, parainfluenza viruses types 1-4, human metapneumovirus, coronaviruses, rhinoviruses, and adenoviruses. Physical exams and symptom surveys were used to identify respiratory signs and symptoms.
Upper airway samples were collected at 359 visits; concordance of PCR-based viral detection was examined in a subset of paired upper airway and sputum samples from 21 participants at 92 visits. Rhinovirus was the most commonly detected virus (23·1% overall), and rhinovirus detection was the same for both sample types (21·7% each). Sensitivity and specificity for the detection of rhinovirus in sputum relative to upper airway sampling were 70% and 91·7%, respectively. Respiratory symptoms associated with rhinovirus detection included increased cough, increased nasal congestion, increased sputum production, and wheezing.
A relatively high frequency of rhinovirus detection was observed by either upper airway or sputum samples, and clinical findings suggest a significant-associated symptom burden.
Influenza and Other Respiratory Viruses 09/2011; 6(3):218-23. · 4.16 Impact Factor
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Miriam M Treggiari,
George Retsch-Bogart,
Nicole Mayer-Hamblett,
Umer Khan,
Michal Kulich,
Richard Kronmal,
Judy Williams,
Peter Hiatt, Ronald L Gibson,
Terry Spencer,
David Orenstein,
Barbara A Chatfield,
Deborah K Froh,
Jane L Burns,
Margaret Rosenfeld,
Bonnie W Ramsey
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ABSTRACT: To investigate the efficacy and safety of 4 antipseudomonal treatments in children with cystic fibrosis with recently acquired Pseudomonas aeruginosa infection.
Randomized controlled trial.
Multicenter trial in the United States.
Three hundred four children with cystic fibrosis aged 1 to 12 years within 6 months of P aeruginosa detection.
Participants were randomized to 1 of 4 antibiotic regimens for 18 months (six 12-week quarters) between December 2004 and June 2009. Participants randomized to cycled therapy received tobramycin inhalation solution (300 mg twice a day) for 28 days, with oral ciprofloxacin (15-20 mg/kg twice a day) or oral placebo for 14 days every quarter, while participants randomized to culture-based therapy received the same treatments only during quarters with positive P aeruginosa cultures.
The primary end points were time to pulmonary exacerbation requiring intravenous antibiotics and proportion of P aeruginosa -positive cultures.
The intention-to-treat analysis included 304 participants. There was no interaction between treatments. There were no statistically significant differences in exacerbation rates between cycled and culture-based groups (hazard ratio, 0.95; 95% confidence interval [CI], 0.54-1.66) or ciprofloxacin and placebo (hazard ratio, 1.45; 95% CI, 0.82-2.54). The odds ratios of P aeruginosa- positive culture comparing the cycled vs culture-based group were 0.78 (95% CI, 0.49-1.23) and 1.10 (95% CI, 0.71-1.71) comparing ciprofloxacin vs placebo. Adverse events were similar across groups.
No difference in the rate of exacerbation or prevalence of P aeruginosa positivity was detected between cycled and culture-based therapies. Adding ciprofloxacin produced no benefits.
ClinicalTrials.gov Identifier: NCT00097773.
Archives of pediatrics & adolescent medicine 09/2011; 165(9):847-56. · 3.73 Impact Factor
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ABSTRACT: The risk of pulmonary exacerbation following Pseudomonas aeruginosa (Pa) acquisition in children with cystic fibrosis (CF) is unknown.
To determine if failure of antibiotic therapy to eradicate Pa and frequency of Pa recurrence are associated with increased exacerbation risk.
The cohort included 282 children with CF who participated in the EPIC trial ages 1-12 with newly acquired Pa, defined as either a first lifetime Pa positive respiratory culture or positive after two years of negative cultures (past isolation of Pa but >2 years prior to the trial). All received antibiotics to promote initial eradication followed by 15 months of intermittent maintenance antibiotics. Quarterly cultures were used to define initial eradication success and subsequent number of Pa recurrences. A standardized symptom-based definition of exacerbation was utilized. Cox proportional hazards models were used to estimate exacerbation risk.
Failure to initially eradicate Pa was associated with exacerbation risk (hazard ratio [HR]: 2.49, 95% confidence interval [CI] 1.26, 4.93). In 245/282 with successful initial eradication during the trial, past isolation of Pa >2 years before the trial was the most significant predictor of exacerbation (HR 1.62, 95% CI 1.12, 2.35). In 37/282 who failed initial eradication, persistent Pa during the maintenance phase (1 or more Pa recurrences after failure to initially eradicate) added even greater exacerbation risk (HR 4.13, 95% CI 1.28, 13.32).
Children with CF who fail to eradicate after initial antibiotic treatment are at higher risk of subsequent exacerbation, suggesting clinical benefit to successful early eradication of Pa infection.
Pediatric Pulmonology 08/2011; 47(2):125-34. · 2.53 Impact Factor
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ABSTRACT: Aztreonam for inhalation solution (AZLI) is an inhaled antibiotic for patients with cystic fibrosis (CF) and Pseudomonas aeruginosa airway infection. The risk of selecting for P. aeruginosa isolates with reduced susceptibility to antibiotics is inherent to their use, but is of particular concern following repeated exposure and when complete eradication of lung pathogens is difficult to obtain. We investigated whether repeated treatment courses of AZLI led to decreases in P. aeruginosa susceptibility to aztreonam or other antibiotics.
Serial sputum specimens were collected and processed for isolation and quantification of all P. aeruginosa isolates in a Phase 3 open-label, 18 month study (NCT00128492) including 274 CF patients receiving up to nine courses of AZLI twice daily (AZLI2) or thrice daily (AZLI3) (28 days on/28 days off). P. aeruginosa antibiotic susceptibility testing was conducted.
No changes were observed in the aztreonam MIC(50) for all P. aeruginosa isolates collected from AZLI3 patients, while intermittent increases were observed in the aztreonam MIC(90). Approximately 70% of the P. aeruginosa isolates with the highest aztreonam MIC from each patient receiving AZLI3 remained unchanged or decreased relative to that patient's equivalent isolate at baseline; 30% experienced an increase in MIC. Few decreases in P. aeruginosa susceptibility to other antibiotics were observed in AZLI3 patients, while increases in P. aeruginosa susceptibility to tobramycin were observed.
Few decreases in aztreonam susceptibility were reported in patients receiving AZLI3. Increases in tobramycin susceptibility were observed, suggesting that novel treatment paradigms may be able to prolong antibiotic susceptibility in CF patients.
Journal of Antimicrobial Chemotherapy 07/2011; 66(10):2398-404. · 5.07 Impact Factor
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Samuel M. Moskowitz MD,
MPH Julia C. Emerson MD,
Sharon McNamara MN,
Richard D. Shell MD,
David M. Orenstein MD,
Daniel Rosenbluth MD,
Marcia F. Katz MD,
Richard Ahrens MD,
Douglas Hornick MD,
Patricia M. Joseph MD, [......],
David M. Orenstein,
Daniel Rosenbluth,
Marcia F. Katz,
Richard Ahrens,
Douglas Hornick,
Patricia M. Joseph, Ronald L. Gibson,
Moira L. Aitken,
Wade W. Benton,
Jane L. Burns
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ABSTRACT: RationaleIn cystic fibrosis (CF), conventional antibiotic susceptibility results correlate poorly with clinical outcomes. We hypothesized that biofilm testing would more accurately reflect the susceptibilities of bacteria infecting CF airways.MethodsA multicenter randomized pilot trial was conducted to assess the efficacy and safety of using biofilm susceptibility testing of Pseudomonas aeruginosa sputum isolates to guide antibiotic regimens for chronic airway infections in clinically stable adolescent and adult CF patients. Thirty-nine participants were randomized to biofilm or conventional treatment groups; 14-day courses of two antibiotics were selected according to an activity-based algorithm using the corresponding susceptibility results.ResultsOf the agents tested, meropenem was most active against biofilm-grown bacteria, and was included in regimens for about half of each study group. For 19 of 39 randomized participants, randomization to the other study group would not have changed the antibiotic classes of the assigned regimen. Study groups were comparable at baseline, and had similar mean decreases in bacterial density, measured in log10 colony forming units per gram of sputum (biofilm, −2.94 [SD 2.83] vs. conventional, −3.27 [SD 3.09]), and mean increases in forced expiratory volume in 1 sec, measured in liters (0.18 [SD 0.20] vs. 0.12 [SD 0.22]).Conclusions
In this pilot study, antibiotic regimens based on biofilm testing did not differ significantly from regimens based on conventional testing in terms of microbiological and clinical responses. The predictive value of biofilm testing may nonetheless warrant evaluation in an adequately powered clinical trial in younger CF patients or those experiencing acute pulmonary exacerbation. Pediatr. Pulmonol. 2011; 46:184–192. © 2011 Wiley-Liss, Inc.
Pediatric Pulmonology 01/2011; 46(2):184 - 192. · 2.53 Impact Factor
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ABSTRACT: Chronic airway infection with Pseudomonas aeruginosa (PA) causes morbidity and mortality in patients with cystic fibrosis (CF). Additional anti-PA therapies are needed to improve health status and health-related quality of life. AIR-CF3 was an international 18-month, open-label study to evaluate the safety and efficacy of repeated courses of aztreonam for inhalation solution (AZLI, now marketed as Cayston®) in patients aged ≥ 6 years with CF and PA infection who previously participated in one of two Phase 3 studies: AIR-CF1 or AIR-CF2. Patients received up to nine courses (28 days on/28 days off) of 75 mg AZLI two (BID) or three times daily (TID) based on randomization in the previous trials. 274 patients, mean age 28.5 years (range: 8-74 years), participated. Mean treatment adherence was high (92.0% BID group, 88.0% TID group). Hospitalization rates were low and adverse events were consistent with CF. With each course of AZLI, FEV(1) and scores on the Cystic Fibrosis Questionnaire-Revised Respiratory Symptom scale improved and bacterial density in sputum was reduced. Benefits waned in the 28 days off therapy, but weight gain was sustained over the 18 months. There were no sustained decreases in PA susceptibility. A dose response was observed; AZLI TID-treated patients demonstrated greater improvements in lung function and respiratory symptoms over 18 months. Repeated intermittent 28-day courses of AZLI treatment were well tolerated. Clinical benefits in pulmonary function, health-related quality of life, and weight were observed with each course of therapy. AZLI is a safe and effective new therapy in patients with CF and PA airway infection.
Pediatric Pulmonology 11/2010; 45(11):1121-34. · 2.53 Impact Factor
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Samuel M Moskowitz,
Julia C Emerson,
Sharon McNamara,
Richard D Shell,
David M Orenstein,
Daniel Rosenbluth,
Marcia F Katz,
Richard Ahrens,
Douglas Hornick,
Patricia M Joseph, Ronald L Gibson,
Moira L Aitken,
Wade W Benton,
Jane L Burns
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[hide abstract]
ABSTRACT: In cystic fibrosis (CF), conventional antibiotic susceptibility results correlate poorly with clinical outcomes. We hypothesized that biofilm testing would more accurately reflect the susceptibilities of bacteria infecting CF airways.
A multicenter randomized pilot trial was conducted to assess the efficacy and safety of using biofilm susceptibility testing of Pseudomonas aeruginosa sputum isolates to guide antibiotic regimens for chronic airway infections in clinically stable adolescent and adult CF patients. Thirty-nine participants were randomized to biofilm or conventional treatment groups; 14-day courses of two antibiotics were selected according to an activity-based algorithm using the corresponding susceptibility results.
Of the agents tested, meropenem was most active against biofilm-grown bacteria, and was included in regimens for about half of each study group. For 19 of 39 randomized participants, randomization to the other study group would not have changed the antibiotic classes of the assigned regimen. Study groups were comparable at baseline, and had similar mean decreases in bacterial density, measured in log(10) colony forming units per gram of sputum (biofilm, -2.94 [SD 2.83] vs. conventional, -3.27 [SD 3.09]), and mean increases in forced expiratory volume in 1 sec, measured in liters (0.18 [SD 0.20] vs. 0.12 [SD 0.22]).
In this pilot study, antibiotic regimens based on biofilm testing did not differ significantly from regimens based on conventional testing in terms of microbiological and clinical responses. The predictive value of biofilm testing may nonetheless warrant evaluation in an adequately powered clinical trial in younger CF patients or those experiencing acute pulmonary exacerbation.
Pediatric Pulmonology 10/2010; 46(2):184-92. · 2.53 Impact Factor
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Margaret Rosenfeld,
Julia Emerson,
Sharon McNamara,
Kelli Joubran,
George Retsch-Bogart,
Gavin R Graff,
Hector H Gutierrez,
Jamshed F Kanga,
Thomas Lahiri,
Blake Noyes,
Bonnie Ramsey,
Clement L Ren,
Michael Schechter,
Wayne Morgan, Ronald L Gibson
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ABSTRACT: The EPIC Observational Study is an ongoing prospective cohort study investigating risk factors for and clinical outcomes associated with early Pseudomonas aeruginosa (Pa) acquisition in young children with cystic fibrosis (CF).
To describe the baseline characteristics of the cohort and evaluate associations between potential risk factors and nutritional and respiratory characteristics at enrollment. We hypothesized that distinct demographic and environmental risk factors could be identified for poorer nutritional status and lung function at enrollment.
During 2004-2006, 1,700 children with CF were enrolled at 59 US CF centers. Children <or=12 years were eligible if they had no prior Pa infection (Pa-Never) or, if prior isolation of Pa from respiratory cultures, at least a 2-year history of Pa negative cultures (Pa-Past).
One thousand one hundred seventeen participants (65.7%) were Pa-Never and 583 (34.3%) Pa-Past. Pa-never patients had a lower proportion of CFTR genotypes with both mutations in functional classes I, II, or III), higher lung function and less respiratory symptoms. Diagnosis after newborn or prenatal screening was associated with significantly higher mean weight, height, and FEV(1) at enrollment, while maternal smoking during pregnancy appeared to worsen these parameters.
Children in this cohort with a remote history of Pa infection had a higher proportion of CFTR genotypes associated with severely reduced CFTR function as well as lower lung function and more respiratory symptoms than those without prior Pa infection. These observed differences in respiratory indices may reflect the impact of prior Pa airway infection and/or of CFTR genotype or other genetic factors predisposing both to earlier Pa acquisition and more severe lung disease. Key characteristics associated with nutritional and pulmonary status at enrollment included diagnosis after prenatal or neonatal screening (protective) and in utero cigarette exposure (harmful).
Pediatric Pulmonology 09/2010; 45(9):934-44. · 2.53 Impact Factor
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ABSTRACT: Lung function (FEV(1)) generally improves during treatment of pulmonary exacerbations in patients with cystic fibrosis (CF). However, it is unclear how often return to previous baseline FEV(1) is achieved.
(1) To determine the proportion of pediatric patients with CF treated for a pulmonary exacerbation who fail to recover to baseline FEV(1) and (2) to identify factors associated with this failure.
We performed a case-control analysis of patients from a single pediatric CF center admitted for their first pulmonary exacerbation in 2001-2006. Patients were considered to have recovered to baseline FEV(1) if their best FEV(1) within the 3 months following treatment was >or=95% of the best FEV(1) during the 6 months prior to treatment. Logistic regression was used to estimate associations between clinical characteristics and failure to regain baseline FEV(1).
Of 104 patients, 24 (23.1%) did not recover to baseline FEV(1). The adjusted odds ratio of failure to recover to baseline FEV(1) was 1.49 (95% confidence interval [CI] 1.20, 1.86) for every 5% greater decline in FEV(1) from baseline to admission. In exploratory analyses, the adjusted odds ratios for the failure to recover to baseline were also significantly higher for patients who were evaluated in our CF clinic more frequently between the baseline measurement and admission, were younger, or were insured by Medicaid.
Approximately one in four patients with CF failed to recover to baseline lung function after a pulmonary exacerbation despite treatment with intravenous antibiotics. Failure to recover to baseline was associated with the degree of decline in FEV(1) that had occurred prior to hospital admission, suggesting opportunities for earlier intervention to improve lung function outcomes. Additional studies are needed to determine how the failure to recover to baseline affects subsequent FEV(1) decline.
Pediatric Pulmonology 02/2010; 45(2):127-34. · 2.53 Impact Factor
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ABSTRACT: Chronic airway infection with Pseudomonas aeruginosa (PA) causes morbidity and mortality in patients with cystic fibrosis (CF). Additional anti-PA therapies are needed to improve health status and health-related quality of life. AIR-CF3 was an international 18-month, open-label study to evaluate the safety and efficacy of repeated courses of aztreonam for inhalation solution (AZLI, now marketed as Cayston 1) in patients aged !6 years with CF and PA infection who previously participated in one of two Phase 3 studies: AIR-CF1 or AIR-CF2. Patients received up to nine courses (28 days on/28 days off) of 75 mg AZLI two (BID) or three times daily (TID) based on randomization in the previous trials. 274 patients, mean age 28.5 years (range: 8–74 years), participated. Mean treatment adherence was high (92.0% BID group, 88.0% TID group). Hospi-talization rates were low and adverse events were consistent with CF. With each course of AZLI, FEV 1 and scores on the Cystic Fibrosis Questionnaire-Revised Respiratory Symptom scale improved and bacterial density in sputum was reduced. Benefits waned in the 28 days off therapy, but weight gain was sustained over the 18 months. There were no sustained decreases in PA susceptibility. A dose response was observed; AZLI TID-treated patients demonstrated greater improvements in lung function and respiratory symptoms over 18 months. Repeated intermittent 28-day courses of AZLI treatment were well tolerated. Clinical benefits in pulmonary function, health-related quality of life, and weight were observed with each course of therapy. AZLI is a safe and effective new therapy in patients with CF and PA airway infection. Pediatr Pulmonol. 2010; 45:1121–1134.
Pediatric Pulmonology. 01/2010; 45:1121-1134.
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ABSTRACT: We assessed the short-term efficacy and safety of aztreonam lysine for inhalation (AZLI [an aerosolized monobactam antibiotic]) in patients with cystic fibrosis (CF) and Pseudomonas aeruginosa (PA) airway infection.
In this randomized, double-blind, placebo-controlled, international study (AIR-CF1 trial; June 2005 to April 2007), patients (n = 164; >or= 6 years of age) with FEV(1) >or= 25% and <or= 75% predicted values, and no recent use of antipseudomonal antibiotics or azithromycin were treated with 75 mg of AZLI (three times daily for 28 days) or placebo (1:1 randomization), then were monitored for 14 days after study drug completion. The primary efficacy end point was change in patient-reported respiratory symptoms (CF-Questionnaire-Revised [CFQ-R] Respiratory Scale). Secondary end points included changes in pulmonary function (FEV(1)), sputum PA density, and nonrespiratory CFQ-R scales. Adverse events and minimum inhibitory concentrations of aztreonam for PA were monitored.
After 28 days of treatment, AZLI improved the mean CFQ-R respiratory score (9.7 points; p < 0.001), FEV(1) (10.3% predicted; p < 0.001), and sputum PA density (- 1.453 log(10) cfu/g; p < 0.001), compared with placebo. Significant improvements in Eating, Emotional Functioning, Health Perceptions, Physical Functioning, Role Limitation/School Performance, and Vitality CFQ-R scales were observed. Adverse events were consistent with symptoms of CF lung disease and were comparable for AZLI and placebo except the incidence of "productive cough" was reduced by half in AZLI-treated patients. PA aztreonam susceptibility at baseline and end of therapy were similar.
In patients with CF, PA airway infection, moderate-to-severe lung disease, and no recent use of antipseudomonal antibiotics or azithromycin, 28-day treatment with AZLI significantly improved respiratory symptoms and pulmonary function, and was well tolerated. Trial registration: Clinicaltrials.gov Identifier: NCT00112359.
Chest 05/2009; 135(5):1223-32. · 5.25 Impact Factor
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ABSTRACT: The primary cause of morbidity and mortality in patients with cystic fibrosis (CF) is progressive obstructive pulmonary disease due to chronic endobronchial infection, particularly with Pseudomonas aeruginosa (Pa). Risk factors for and clinical impact of early Pa infection in young CF patients are less well understood.
The present studies are designed to evaluate risk factors and outcomes associated with early Pa acquisition, and the benefits and harms of four anti-pseudomonal treatment regimens in young CF patients initiated after the first Pa positive respiratory culture.
The Early Pseudomonas Infection Control (EPIC) program consists of two studies, a randomized multicenter trial in CF patients ages 1-12 years at first isolation of Pa from a respiratory culture, and a longitudinal cohort study enrolling Pa-negative patients. Using a factorial design, trial participants are assigned for 18 months to either anti-pseudomonal treatment on a scheduled quarterly basis (cycled therapy) or based on recovery of Pa from quarterly respiratory cultures (culture-based therapy). The study drugs include inhaled tobramycin (300 mg BID) for 28 days, combined with either oral ciprofloxacin (15-20 mg/kg BID) or oral placebo for 14 days. The primary endpoints of the trial are the time to pulmonary exacerbation requiring IV antibiotics or hospitalization for respiratory symptoms, and the proportion of patients with new Pa-positive respiratory cultures during the study. The broad goals of the observational study are to describe the risk factors and outcomes associated with early acquisition of Pa. 306 patients were randomized in the clinical trial and 1787 were enrolled in the cohort study.
These companion studies will provide valuable epidemiological and microbiological information on early CF lung disease and Pa acquisition, and safety and clinical efficacy data on anti-pseudomonal treatment strategies for early Pa infections in the airways of young children with CF.
Contemporary clinical trials 02/2009; 30(3):256-68. · 1.51 Impact Factor
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ABSTRACT: The effectiveness and safety of aztreonam lysine for inhalation (AZLI) in patients with cystic fibrosis (CF) on maintenance treatment for Pseudomonas aeruginosa (PA) airway infection was evaluated in this randomized, double-blind, placebo-controlled study.
To evaluate the safety and efficacy of inhaled aztreonam lysine in controlling PA infection in patients with CF.
After randomization and a 28-day course of tobramycin inhalation solution (TIS), patients (n = 211; > or =6 yr; > or =3 TIS courses within previous year; FEV(1) > or = 25% and < or =75% predicted values) were treated with 75 mg AZLI or placebo, twice or three times daily for 28 days, then monitored for 56 days. The primary efficacy endpoint was time to need for additional inhaled or intravenous antipseudomonal antibiotics. Secondary endpoints included changes in respiratory symptoms (CF Questionnaire-Revised [CFQ-R] Respiratory Scale), pulmonary function (FEV(1)), and sputum PA density. Adverse events and minimum inhibitory concentrations of aztreonam for PA were monitored.
AZLI treatment increased median time to need for additional antipseudomonal antibiotics for symptoms of pulmonary exacerbation by 21 days, compared with placebo (AZLI, 92 d; placebo, 71 d; P = 0.007). AZLI improved mean CFQ-R respiratory scores (5.01 points, P = 0.02), FEV(1) (6.3%, P = 0.001), and sputum PA density (-0.66 log(10) cfu/g, P = 0.006) compared with placebo; no AZLI dose-response was observed. Adverse events reported for AZLI and placebo were comparable and consistent with CF lung disease. Susceptibility of PA to aztreonam at baseline and end of therapy were similar.
AZLI was effective in patients with CF using frequent TIS therapy. AZLI delayed time to need for inhaled or intravenous antipseudomonal antibiotics, improved respiratory symptoms and pulmonary function, and was well tolerated. Clinical trial registered with www.clinicaltrials.gov (NCT 00104520).
American Journal of Respiratory and Critical Care Medicine 11/2008; 178(9):921-8. · 11.08 Impact Factor
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ABSTRACT: To assess the effects of Pseudomonas aeruginosa and Staphylococcus aureus infection on lower airway inflammation and clinical status in young children with cystic fibrosis (CF).
We studied 111 children age < 6 years who had 2 P aeruginosa-positive oropharyngeal cultures within 12 months. We examined bronchoalveolar lavage fluid (BALF) inflammatory markers (ie, cell count, differential, interleukin [IL]-8, IL-6, neutrophil elastase), CF-related bacterial pathogens, exotoxin A serology, and clinical indicators of disease severity.
Young children with CF with both upper and lower airway P aeruginosa infection had higher neutrophil counts, higher IL-8 and free neutrophil elastase levels, increased likelihood of positive exotoxin A titers, and lower Shwachman scores compared with those with positive upper airway cultures only. S aureus was associated with increased lower airway inflammation, and the presence of both P aeruginosa and S aureus had an additive effect on concentrations of lower airway inflammatory markers. BALF markers of inflammation were increased with the number of different bacterial pathogens detected.
Young children with CF who have upper and lower airway P aeruginosa infection have increased endobronchial inflammation and poorer clinical status compared with those with only upper airway P aeruginosa infection. The independent and additive effects of S aureus on inflammation support the significance of polymicrobial infection in early CF lung disease.
The Journal of pediatrics 10/2008; 154(2):183-8. · 4.02 Impact Factor
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ABSTRACT: Aztreonam lysine for inhalation (AZLI) is being developed for treatment of CF patients with Pseudomonas aeruginosa airway infection.
This double-blind, randomized, placebo-controlled Phase 2 study evaluated the safety, tolerability and efficacy of 75 and 225 mg AZLI administered BID for 14 days using the eFlow Electronic Nebulizer (Pari Innovative Manufacturers, Inc., Midlothian, VA). Patients were 13 years and older with FEV1>or=40% predicted, chronic P. aeruginosa infection, and had used no anti-pseudomonal antibiotics for 56 days.
Of 131 patients screened, 105 received AZLI or placebo. Mean age was 26 years and mean FEV1 percent predicted was 77% at baseline. There was a statistically significant reduction, compared to placebo, in P. aeruginosa CFU density in each AZLI group at Days 7 and 14 (P<0.001). The planned primary analysis, percent change in FEV1 at Day 14, demonstrated no statistically significant difference. Post hoc analysis demonstrated significant increase in FEV1 at Day 7 for the subset of patients with baseline FEV1<75% predicted in the 225 mg AZLI group. Bronchodilator use was associated with greater improvement in FEV1, as well as greater reduction in P. aeruginosa bacterial density and higher plasma aztreonam concentrations in the 225 mg AZLI group. Adverse events were similar between placebo and AZLI although there was a trend toward increased respiratory symptoms in the 225 mg AZLI group.
These data support the further development of AZLI and provide information for the design of subsequent studies.
Pediatric Pulmonology 01/2008; 43(1):47-58. · 2.53 Impact Factor
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ABSTRACT: Aminoglycosides are commonly used in cystic fibrosis patients to treat Pseudomonas aeruginosa respiratory infections. Aminoglycoside-induced hearing loss may occur in 1%-15% of patients with cystic fibrosis, ranging from mild to severe. Recently, a genetic test to identify patients with a mitochondrial mutation (A1555G) that may predispose patients to this adverse event has become available. Although the A1555G variant is very rare, it seems to confer a high risk of severe hearing loss in patients exposed to aminoglycosides.
The objective was to evaluate the potential clinical, patient, and economic outcomes associated with the use of A1555G testing in a cystic fibrosis population, and explore data gaps and uncertainty in its clinical implementation.
We developed a decision-analytic model to evaluate a hypothetical cohort of patients with cystic fibrosis from a societal perspective. Clinical and economic data were derived primarily from a critical literature review. The incidence of aminoglycoside-induced severe hearing loss, quality-adjusted life-years, and total health care costs were evaluated. Sensitivity analyses were conducted to evaluate uncertainty in our results.
In the base-case analysis, A1555G testing decreased the risk of severe aminoglycoside-induced hearing loss by 0.12% in the cystic fibrosis population. The discounted incremental cost per quality-adjusted life-years gained was $79,300, but varied widely from $33,000 to testing being dominated by the no testing strategy (higher costs and lower quality-adjusted life-years with testing) in sensitivity analyses. If avoidance of aminoglycosides in patients testing positive leads to an absolute increase in the lifetime risk of death from Pseudomonas infection of 0.8% or greater, A1555G testing would lead to a decrease in quality-adjusted life-years.
The results of our analysis suggest that there are significant data gaps and uncertainty in the outcomes with A1555G testing, but it is not likely cost-effective, and could lead to worse patient outcomes due to avoidance of first-line therapy in the >95% of patients who are false-positives. Additional research is needed before pharmacogenetic testing for the A1555G mitochondrial mutation can be recommended, even in a population with a high likelihood of exposure to aminoglycosides.
Genetics in medicine: official journal of the American College of Medical Genetics 11/2007; 9(10):695-704. · 3.92 Impact Factor
