Dataset Information

Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis.

ABSTRACT:

Objective

To investigate the efficacy and safety of 4 antipseudomonal treatments in children with cystic fibrosis with recently acquired Pseudomonas aeruginosa infection.

Design

Randomized controlled trial.

Setting

Multicenter trial in the United States.

Participants

Three hundred four children with cystic fibrosis aged 1 to 12 years within 6 months of P aeruginosa detection.

Interventions

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.

Main outcome measures

The primary end points were time to pulmonary exacerbation requiring intravenous antibiotics and proportion of P aeruginosa -positive cultures.

Results

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.

Conclusions

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.

Trial registration

ClinicalTrials.gov Identifier: NCT00097773.

SUBMITTER: Treggiari MM

PROVIDER: S-EPMC3991697 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Publications

Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis.

Treggiari Miriam M MM Retsch-Bogart George G Mayer-Hamblett Nicole N Khan Umer U Kulich Michal M Kronmal Richard R Williams Judy J Hiatt Peter P Gibson Ronald L RL Spencer Terry T Orenstein David D Chatfield Barbara A BA Froh Deborah K DK Burns Jane L JL Rosenfeld Margaret M Ramsey Bonnie W BW

Archives of pediatrics & adolescent medicine 20110901 9

<h4>Objective</h4>To investigate the efficacy and safety of 4 antipseudomonal treatments in children with cystic fibrosis with recently acquired Pseudomonas aeruginosa infection.<h4>Design</h4>Randomized controlled trial.<h4>Setting</h4>Multicenter trial in the United States.<h4>Participants</h4>Three hundred four children with cystic fibrosis aged 1 to 12 years within 6 months of P aeruginosa detection.<h4>Interventions</h4>Participants were randomized to 1 of 4 antibiotic regimens for 18 month ...[more]

PMID: 21893650

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Project description:BackgroundWe 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.MethodsIn 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.ResultsAfter 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.ConclusionsIn 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 registrationClinicaltrials.gov Identifier: NCT00112359.

Project description:Pseudomonas aeruginosa is an opportunistic pathogen which is evolving resistance to many currently used antibiotics. While much research has been devoted to the roles of pathogenic P. aeruginosa in cystic fibrosis (CF) patients, less is known of its ecological properties. P. aeruginosa dominates the lungs during chronic infection in CF patients, yet its abundance in some environments is less than that of other diverse groups of pseudomonads. Here, we sought to determine if clinical isolates of P. aeruginosa are vulnerable to environmental pseudomonads that dominate soil and water habitats in one-to-one competitions which may provide a source of inhibitory factors. We isolated a total of 330 pseudomonads from diverse habitats of soil and freshwater ecosystems and competed these strains against one another to determine their capacity for antagonistic activity. Over 900 individual inhibitory events were observed. Extending the analysis to P. aeruginosa isolates revealed that clinical isolates, including ones with increased alginate production, were susceptible to competition by multiple environmental strains. We performed transposon mutagenesis on one isolate and identified an ∼14.8-kb locus involved in antagonistic activity. Only two other environmental isolates were observed to carry the locus, suggesting the presence of additional unique compounds or interactions among other isolates involved in outcompeting P. aeruginosa This collection of strains represents a source of compounds that are active against multiple pathogenic strains. With the evolution of resistance of P. aeruginosa to currently used antibiotics, these environmental strains provide opportunities for novel compound discovery against drug-resistant clinical strains.ImportanceWe demonstrate that clinical CF-derived isolates of P. aeruginosa are susceptible to competition in the presence of environmental pseudomonads. We observed that many diverse environmental strains exhibited varied antagonistic profiles against a panel of clinical P. aeruginosa isolates, suggesting the presence of distinct mechanisms of inhibition among these ecological strains. Understanding the properties of these antagonistic events offers the potential for discoveries of antimicrobial compounds or metabolic pathways important to the development of novel treatments for P. aeruginosa infections.

Dataset Information

Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis.

Objective

Design

Setting

Participants

Interventions

Main outcome measures

Results

Conclusions

Trial registration

Publications

Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis.

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