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Pseudomonas aeruginosa phenotypes associated with eradication failure in children with cystic fibrosis.

ABSTRACT: Pseudomonas aeruginosa is a key respiratory pathogen in people with cystic fibrosis (CF). Due to its association with lung disease progression, initial detection of P. aeruginosa in CF respiratory cultures usually results in antibiotic treatment with the goal of eradication. Pseudomonas aeruginosa exhibits many different phenotypes in vitro that could serve as useful prognostic markers, but the relative relationships between these phenotypes and failure to eradicate P. aeruginosa have not been well characterized.We measured 22 easily assayed in vitro phenotypes among the baseline P. aeruginosa isolates collected from 194 participants in the 18-month EPIC clinical trial, which assessed outcomes after antibiotic eradication therapy for newly identified P. aeruginosa. We then evaluated the associations between these baseline isolate phenotypes and subsequent outcomes during the trial, including failure to eradicate after antipseudomonal therapy, emergence of mucoidy, and occurrence of an exacerbation.Baseline P. aeruginosa isolates frequently exhibited phenotypes thought to represent chronic adaptation, including mucoidy. Wrinkly colony surface and irregular colony edges were both associated with increased risk of eradication failure (hazard ratios [95% confidence intervals], 1.99 [1.03-3.83] and 2.14 [1.32-3.47], respectively). Phenotypes reflecting defective quorum sensing were significantly associated with subsequent mucoidy, but no phenotype was significantly associated with subsequent exacerbations during the trial.Pseudomonas aeruginosa phenotypes commonly considered to reflect chronic adaptation were observed frequently among isolates at early detection. We found that 2 easily assayed colony phenotypes were associated with failure to eradicate after antipseudomonal therapy, both of which have been previously associated with altered biofilm formation and defective quorum sensing.

SUBMITTER: Mayer-Hamblett N

PROVIDER: S-EPMC4148602 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Pseudomonas aeruginosa phenotypes associated with eradication failure in children with cystic fibrosis.

Mayer-Hamblett Nicole N Ramsey Bonnie W BW Kulasekara Hemantha D HD Wolter Daniel J DJ Houston Laura S LS Pope Christopher E CE Kulasekara Bridget R BR Armbruster Catherine R CR Burns Jane L JL Retsch-Bogart George G Rosenfeld Margaret M Gibson Ronald L RL Miller Samuel I SI Khan Umer U Hoffman Lucas R LR

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20140526 5

<h4>Background</h4>Pseudomonas aeruginosa is a key respiratory pathogen in people with cystic fibrosis (CF). Due to its association with lung disease progression, initial detection of P. aeruginosa in CF respiratory cultures usually results in antibiotic treatment with the goal of eradication. Pseudomonas aeruginosa exhibits many different phenotypes in vitro that could serve as useful prognostic markers, but the relative relationships between these phenotypes and failure to eradicate P. aerugin ...[more]

PMID: 24863401

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Project description:BACKGROUND:Chronic pulmonary infection with Pseudomonas aeruginosa is one of the most important causes of mortality and morbidity in cystic fibrosis. If antibiotics are commenced promptly, infection can be eradicated. The aim of the trial was to compare the effectiveness and safety of intravenous ceftazidime and tobramycin versus oral ciprofloxacin in the eradication of P aeruginosa. METHODS:We did a multicentre, parallel group, open-label, randomised controlled trial in 72 cystic fibrosis centres (70 in the UK and two in Italy). Eligible participants were older than 28 days with an isolate of P aeruginosa (either the first ever isolate or a new isolate after at least 1 year free of infection). Participants were excluded if the P aeruginosa was resistant to, or they had a contraindication to, one or more of the trial antibiotics; if they were already receiving P aeruginosa suppressive therapy; if they had received any P aeruginosa eradication therapy within the previous 9 months; or if they were pregnant or breastfeeding. We used web-based randomisation to assign patients to 14 days intravenous ceftazidime and tobramycin or 12 weeks oral ciprofloxacin. Both were combined with 12 weeks inhaled colistimethate sodium. Randomisation lists were generated by a statistician, who had no involvement in the trial, using a computer-generated list. Randomisation was stratified by centre and because of the nature of the interventions, blinding was not possible. Our primary outcome was eradication of P aeruginosa at 3 months and remaining free of infection to 15 months. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who received at least one dose of study drug. TORPEDO-CF was registered on the ISRCTN register, ISRCTN02734162, and EudraCT, 2009-012575-10. FINDINGS:Between Oct 5, 2010, and Jan 27, 2017, 286 patients were randomly assigned to treatment: 137 to intravenous antibiotics and 149 to oral antibiotics. 55 (44%) of 125 participants in the intravenous group and 68 (52%) of 130 participants in the oral group achieved the primary outcome. Participants randomly assigned to the intravenous group were less likely to achieve the primary outcome, although the difference between groups was not statistically significant (relative risk 0·84, 95% CI 0·65-1·09; p=0·18). 11 serious adverse events occurred in ten (8%) of 126 participants in the intravenous antibiotics group and 17 serious adverse events in 12 (8%) of 146 participants in the oral antibiotics group. INTERPRETATION:Compared with oral therapy, intravenous antibiotics did not achieve sustained eradication of P aeruginosa in a greater proportion of patients with cystic fibrosis and was more expensive. Although there were fewer hospitalisations in the intravenous group than the oral group during follow-up, this confers no advantage over oral treatment because intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P aeruginosa in cystic fibrosis. FUNDING:National Institute for Health Research Health Technology Assessment Programme.

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Pseudomonas aeruginosa phenotypes associated with eradication failure in children with cystic fibrosis.

Publications

Pseudomonas aeruginosa phenotypes associated with eradication failure in children with cystic fibrosis.

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