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Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial.

ABSTRACT: 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.

SUBMITTER: Hewer SCL

PROVIDER: S-EPMC7606906 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial.

Hewer Simon C Langton SCL Smyth Alan R AR Brown Michaela M Jones Ashley P AP Hickey Helen H Kenna Dervla D Ashby Deborah D Thompson Alexander A Williamson Paula R PR

The Lancet. Respiratory medicine 20201001 10

<h4>Background</h4>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.<h4>Methods</h4>We did a multicentre, parallel group, open-label, randomised controlled trial in 72 cystic ...[more]

PMID: 33007285

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Project description:To provide a more detailed survey of adaptive changes in the physiology of P. aeruginosa (PA) during long-term infection of the cystic fibrosis (CF) lung, we performed a comparative proteome and transcriptome analysis of a set of isogenic sequential non-mutator and mutator isolates from three selected CF patients. Recently, we showed that during CF lung persistence PA mutators converge to a virulence-attenuated phenotype. In this study, we demonstrate that besides virulence-associated traits (VATs) the adaptation process of PA predominantly comprises metabolic pathways. In end-stage mutator strains, transcripts of genes encoding VATs, chemotaxis, degradation of aromatic compounds and several two-component regulatory systems were decreased. In contrast, several transcripts of genes or proteins involved in metabolism of fatty acids, nucleotides, amino acids and the generation of energy were increased. Of particular interest is the increased expression level of genes involved in (i) the anaerobic arginine-deiminase pathway, (ii) the anaerobic respiration such as nitrate-uptake protein OprF, redox-active azurin and cytchrome c551 peroxidase, (iii) the micro-aerobic respiration such as high oxygen-affinity cytochrome oxidase cbb3 (iv) the tricarboxylic acid cycle (TCA), glyoxylate shunt and anaplerotic carboxylation reactions to oxaloacetate. Strikingly, an increased transcription of the anaerobic regulator gene anr correlates with the up-regulation of ANR-dependent genes. In conclusion, these changes in transcriptome and proteome indicate an adaptive shift towards constitutive expression of genes of metabolic pathways obviously required for growth under micro-aerobic and nutritional conditions of suppurative CF lung tissue. Finally, these results provide us with new targets for antimicrobial agents and biomarkers reflecting adaptation of PA towards progressive CF lung disease. Experiment Overall Design: P. aeruginosa isolates recovered from different time points of chronic cystic fibrosis lung disease were cultered in vitro, harvested for RNA extraction and hybridization on Affymetrix microarrays. We compared the transcriptome (triplicate microarrays) of early non-mutator P. aeruginosa isolates with late mutator isolates with high mutation frequency probably the driving force of an efficient adaptation to changing environements to conclude from differences in gene expression to the requirements of CF lung environment. Experiment Overall Design: Second publication of array data to be added later

Project description:To provide a more detailed survey of adaptive changes in the physiology of P. aeruginosa (PA) during long-term infection of the cystic fibrosis (CF) lung, we performed a comparative proteome and transcriptome analysis of a set of isogenic sequential non-mutator and mutator isolates from three selected CF patients. Recently, we showed that during CF lung persistence PA mutators converge to a virulence-attenuated phenotype. In this study, we demonstrate that besides virulence-associated traits (VATs) the adaptation process of PA predominantly comprises metabolic pathways. In end-stage mutator strains, transcripts of genes encoding VATs, chemotaxis, degradation of aromatic compounds and several two-component regulatory systems were decreased. In contrast, several transcripts of genes or proteins involved in metabolism of fatty acids, nucleotides, amino acids and the generation of energy were increased. Of particular interest is the increased expression level of genes involved in (i) the anaerobic arginine-deiminase pathway, (ii) the anaerobic respiration such as nitrate-uptake protein OprF, redox-active azurin and cytchrome c551 peroxidase, (iii) the micro-aerobic respiration such as high oxygen-affinity cytochrome oxidase cbb3 (iv) the tricarboxylic acid cycle (TCA), glyoxylate shunt and anaplerotic carboxylation reactions to oxaloacetate. Strikingly, an increased transcription of the anaerobic regulator gene anr correlates with the up-regulation of ANR-dependent genes. In conclusion, these changes in transcriptome and proteome indicate an adaptive shift towards constitutive expression of genes of metabolic pathways obviously required for growth under micro-aerobic and nutritional conditions of suppurative CF lung tissue. Finally, these results provide us with new targets for antimicrobial agents and biomarkers reflecting adaptation of PA towards progressive CF lung disease. Keywords: in vitro study/interstrain comparison/clinical isolates/early nonmutator vs. late mutator; variable time point of isolation from cf respiratory secretions

Dataset Information

Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial.

Publications

Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial.

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