Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis.

BACKGROUND: Respiratory tract infections with Pseudomonas aeruginosa occur in most people with cystic fibrosis (CF). Established chronic P aeruginosa infection is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate. This is an updated review. OBJECTIVES: Does giving antibiotics for P aeruginosa infection in people with CF at the time of new isolation improve clinical outcomes (e.g. mortality, quality of life and morbidity), eradicate P aeruginosa infection, and delay the onset of chronic infection, but without adverse effects, compared to usual treatment or an alternative antibiotic regimen? We also assessed cost-effectiveness. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and conference proceedings. Latest search: 24 March 2022. We searched ongoing trials registries. Latest search: 6 April 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people with CF, in whom P aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous (IV) antibiotics with placebo, usual treatment or other antibiotic combinations. We excluded non-randomised trials and cross-over trials. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, assessed risk of bias and extracted data. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 11 trials (1449 participants) lasting between 28 days and 27 months; some had few participants and most had relatively short follow-up periods. Antibiotics in this review are: oral - ciprofloxacin and azithromycin; inhaled - tobramycin nebuliser solution for inhalation (TNS), aztreonam lysine (AZLI) and colistin; IV - ceftazidime and tobramycin. There was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment. Two trials were supported by the manufacturers of the antibiotic used. TNS versus placebo TNS may improve eradication; fewer participants were still positive for P aeruginosa at one month (odds ratio (OR) 0.06, 95% confidence interval (CI) 0.02 to 0.18; 3 trials, 89 participants; low-certainty evidence) and two months (OR 0.15, 95% CI 0.03 to 0.65; 2 trials, 38 participants). We are uncertain whether the odds of a positive culture decrease at 12 months (OR 0.02, 95% CI 0.00 to 0.67; 1 trial, 12 participants). TNS (28 days) versus TNS (56 days) One trial (88 participants) comparing 28 days to 56 days TNS treatment found duration of treatment may make little or no difference in time to next isolation (hazard ratio (HR) 0.81, 95% CI 0.37 to 1.76; low-certainty evidence). Cycled TNS versus culture-based TNS One trial (304 children, one to 12 years old) compared cycled TNS to culture-based therapy and also ciprofloxacin to placebo. We found moderate-certainty evidence of an effect favouring cycled TNS therapy (OR 0.51, 95% CI 0.31 to 0.82), although the trial publication reported age-adjusted OR and no difference between groups. Ciprofloxacin versus placebo added to cycled and culture-based TNS therapy One trial (296 participants) examined the effect of adding ciprofloxacin versus placebo to cycled and culture-based TNS therapy. There is probably no difference between ciprofloxacin and placebo in eradicating P aeruginosa (OR 0.89, 95% CI 0.55 to 1.44; moderate-certainty evidence). Ciprofloxacin and colistin versus TNS We are uncertain whether there is any difference between groups in eradication of P aeruginosa at up to six months (OR 0.43, 95% CI 0.15 to 1.23; 1 trial, 58 participants) or up to 24 months (OR 0.76, 95% CI 0.24 to 2.42; 1 trial, 47 participants); there was a low rate of short-term eradication in both groups. Ciprofloxacin plus colistin versus ciprofloxacin plus TNS One trial (223 participants) found there may be no difference in positive respiratory cultures at 16 months between ciprofloxacin with colistin versus TNS with ciprofloxacin (OR 1.28, 95% CI 0.72 to 2.29; low-certainty evidence). TNS plus azithromycin compared to TNS plus oral placebo Adding azithromycin may make no difference to the number of participants eradicating P aeruginosa after a three-month treatment phase (risk ratio (RR) 1.01, 95% CI 0.75 to 1.35; 1 trial, 91 participants; low-certainty evidence); there was also no evidence of any difference in the time to recurrence. Ciprofloxacin and colistin versus no treatment A single trial only reported one of our planned outcomes; there were no adverse effects in either group. AZLI for 14 days plus placebo for 14 days compared to AZLI for 28 days We are uncertain whether giving 14 or 28 days of AZLI makes any difference to the proportion of participants having a negative respiratory culture at 28 days (mean difference (MD) -7.50, 95% CI -24.80 to 9.80; 1 trial, 139 participants; very low-certainty evidence). Ceftazidime with IV tobramycin compared with ciprofloxacin (both regimens in conjunction with three months colistin) IV ceftazidime with tobramycin compared with ciprofloxacin may make little or no difference to eradication of P aeruginosa at three months, sustained to 15 months, provided that inhaled antibiotics are also used (RR 0.84, 95 % CI 0.65 to 1.09; P = 0.18; 1 trial, 255 participants; high-certainty evidence). The results do not support using IV antibiotics over oral therapy to eradicate P aeruginosa, based on both eradication rate and financial cost. AUTHORS' CONCLUSIONS: We found that nebulised antibiotics, alone or with oral antibiotics, were better than no treatment for early infection with P aeruginosa. Eradication may be sustained in the short term. There is insufficient evidence to determine whether these antibiotic strategies decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of P aeruginosa. One large trial showed that intravenous ceftazidime with tobramycin is not superior to oral ciprofloxacin when inhaled antibiotics are also used. There is still insufficient evidence to state which antibiotic strategy should be used for the eradication of early P aeruginosa infection in CF, but there is now evidence that intravenous therapy is not superior to oral antibiotics.

An unusual cause of stridor.

A 12-month-old infant was referred with a 6-week history of recurrent admissions with worsening stridor. On each previous admission, the stridor responded well, but transiently, to oral dexamethasone. At this presentation, he required high-dependency unit care with high flow oxygen due to marked increased work of breathing.He was born at term, previously well, and up to date with immunisations. There was no significant family history. There were no smokers and two cats at home.He was afebrile with moderate subcostal recession and tracheal tug. On auscultation, breath sounds were normal with transmitted sounds of inspiratory and expiratory stridor. The rest of his examination was normal.He commenced dexamethasone 0.15 µg/kg three times a day, which was weaned as his clinical status improved.Blood tests showed total white cell count 9 x 10ˆ9/L, CRP <1 mg/L, lactate dehydrogenase level and blood film normal. Chest radiograph showed left lung hyperexpansion and apparent right-sided bronchial narrowing (figure 1). Flexible nasendoscopy was unremarkable. Microlaryngoscopy and bronchoscopy showed external airway compression at the level of the carina (figure 2). CT thorax demonstrated a non-enhancing mediastinal mass extrinsic to the airway, approximately 3cmx2.5cmx1.5cm, compressing the carina and main-stem bronchi (figure 3).

Technique, pitfalls, quality, radiation dose and findings of dynamic 4-dimensional computed tomography for airway imaging in infants and children.

This retrospective review of 33 children's dynamic 4-dimensional (4-D) computed tomography (CT) images of the airways, performed using volume scanning on a 320-detector array without anaesthesia (free-breathing) and 1.4-s continuous scanning, was undertaken to report technique, pitfalls, quality, radiation doses and findings. Tracheobronchomalacia (airway diameter collapse >28%) was recorded. Age-matched routine chest CT scans and bronchograms acted as benchmarks for comparing effective dose. Pitfalls included failure to administer intravenous contrast, pull back endotracheal tubes and/or remove nasogastric tubes. Twenty-two studies (67%) were diagnostic. Motion artefact was present in 16 (48%). Mean effective dose: dynamic 4-D CT 1.0 mSv; routine CT chest, 1.0 mSv, and bronchograms, 1.4 mSv. Dynamic 4-D CT showed tracheobronchomalacia in 20 patients (61%) and cardiovascular abnormalities in 12 (36%). Fourteen children (70%) with tracheobronchomalacia were managed successfully by optimising conservative management, 5 (25%) underwent surgical interventions and 1 (5%) died from the presenting disorder.

Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis.

BACKGROUND: Respiratory tract infection with Pseudomonas aeruginosa occurs in most people with cystic fibrosis. Once chronic infection is established, Pseudomonas aeruginosa is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate.This is an update of a Cochrane review first published in 2003, and previously updated in 2006, 2009 and 2014. OBJECTIVES: To determine whether antibiotic treatment of early Pseudomonas aeruginosa infection in children and adults with cystic fibrosis eradicates the organism, delays the onset of chronic infection, and results in clinical improvement. To evaluate whether there is evidence that a particular antibiotic strategy is superior to or more cost-effective than other strategies and to compare the adverse effects of different antibiotic strategies (including respiratory infection with other micro-organisms). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 10 October 2016. SELECTION CRITERIA: We included randomised controlled trials of people with cystic fibrosis, in whom Pseudomonas aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous antibiotics with placebo, usual treatment or other combinations of inhaled, oral or intravenous antibiotics. We excluded non-randomised trials, cross-over trials, and those utilising historical controls. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed risk of bias and extracted data. MAIN RESULTS: The search identified 60 trials; seven trials (744 participants) with a duration between 28 days and 27 months were eligible for inclusion. Three of the trials are over 10 years old and their results may be less applicable today given the changes in standard treatment. Some of the trials had low numbers of participants and most had relatively short follow-up periods; however, there was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment given the interventions and comparators used. Two trials were supported by the manufacturers of the antibiotic used.Evidence from two trials (38 participants) at the two-month time-point showed treatment of early Pseudomonas aeruginosa infection with inhaled tobramycin results in microbiological eradication of the organism from respiratory secretions more often than placebo, odds ratio 0.15 (95% confidence interval (CI) 0.03 to 0.65) and data from one of these trials, with longer follow up, suggested that this effect may persist for up to 12 months.One randomised controlled trial (26 participants) compared oral ciprofloxacin and nebulised colistin versus usual treatment. Results after two years suggested treatment of early infection results in microbiological eradication of Pseudomonas aeruginosa more often than no anti-pseudomonal treatment, odds ratio 0.12 (95% CI 0.02 to 0.79).One trial comparing 28 days to 56 days treatment with nebulised tobramycin solution for inhalation in 88 participants showed that both treatments were effective and well-tolerated, with no notable additional improvement with longer over shorter duration of therapy. However, this trial was not powered to detect non-inferiority or equivalence .A trial of oral ciprofloxacin with inhaled colistin versus nebulised tobramycin solution for inhalation alone (223 participants) failed to show a difference between the two strategies, although it was underpowered to show this. A further trial of inhaled colistin with oral ciprofloxacin versus nebulised tobramycin solution for inhalation with oral ciprofloxacin also showed no superiority of the former, with increased isolation of Stenotrophomonas maltophilia in both groups.A recent, large trial in 306 children aged between one and 12 years compared cycled nebulised tobramycin solution for inhalation to culture-based therapy and also ciprofloxacin to placebo. The primary analysis showed no difference in time to pulmonary exacerbation or proportion of Pseudomonas aeruginosa positive cultures. An analysis performed in this review (not adjusted for age) showed fewer participants in the cycled therapy group with one or more isolates of Pseudomonas aeruginosa, odds ratio 0.51 (95% CI 0.31 to 0.28). Using GRADE, the quality of evidence for outcomes was downgraded to moderate to very low. Downgrading decisions for Pseudomonas aeruginosa eradication and lung function were based on applicability (participants mostly children) and limitations in study design, with imprecision an additional limitation for lung function, growth parameters and adverse effects. AUTHORS' CONCLUSIONS: We found that nebulised antibiotics, alone or in combination with oral antibiotics, were better than no treatment for early infection with Pseudomonas aeruginosa. Eradication may be sustained for up to two years. There is insufficient evidence to determine whether antibiotic strategies for the eradication of early Pseudomonas aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of Pseudomonas aeruginosa. There have been no published randomised controlled trials that investigate the efficacy of intravenous antibiotics to eradicate Pseudomonas aeruginosa in cystic fibrosis. Overall, there is still insufficient evidence from this review to state which antibiotic strategy should be used for the eradication of early Pseudomonas aeruginosa infection in cystic fibrosis.

Cerebro-costo-mandibular syndrome: Clinical, radiological, and genetic findings.

Cerebro-Costo-Mandibular syndrome (CCMS) is a rare autosomal dominant condition comprising branchial arch-derivative malformations with striking rib-gaps. Affected patients often have respiratory difficulties, associated with upper airway obstruction, reduced thoracic capacity, and scoliosis. We describe a series of 12 sporadic and 4 familial patients including 13 infants/children and 3 adults. Severe micrognathia and reduced numbers of ribs with gaps are consistent findings. Cleft palate, feeding difficulties, respiratory distress, tracheostomy requirement, and scoliosis are common. Additional malformations such as horseshoe kidney, hypospadias, and septal heart defect may occur. Microcephaly and significant developmental delay are present in a small minority of patients. Key radiological findings are of a narrow thorax, multiple posterior rib gaps and abnormal costo-transverse articulation. A novel finding in 2 patients is bilateral accessory ossicles arising from the hyoid bone. Recently, specific mutations in SNRPB, which encodes components of the major spliceosome, have been found to cause CCMS. These mutations cluster in an alternatively spliced regulatory exon and result in altered SNRPB expression. DNA was available from 14 patients and SNRPB mutations were identified in 12 (4 previously reported). Eleven had recurrent mutations previously described in patients with CCMS and one had a novel mutation in the alternative exon. These results confirm the specificity of SNRPB mutations in CCMS and provide further evidence for the role of spliceosomal proteins in craniofacial and thoracic development.

Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis.

BACKGROUND: Respiratory tract infection with Pseudomonas aeruginosa occurs in most people with cystic fibrosis. Once chronic infection is established, Pseudomonas aeruginosa is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate.This is an update of a Cochrane review first published in 2003, and previously updated in 2006 and 2009. OBJECTIVES: To determine whether antibiotic treatment of early Pseudomonas aeruginosa infection in children and adults with cystic fibrosis eradicates the organism, delays the onset of chronic infection, and results in clinical improvement. To evaluate whether there is evidence that a particular antibiotic strategy is superior to or more cost-effective than other strategies and to compare the adverse effects of different antibiotic strategies (including respiratory infection with other micro-organisms). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 08 September 2014. SELECTION CRITERIA: We included randomised controlled trials of people with cystic fibrosis, in whom Pseudomonas aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous antibiotics with placebo, usual treatment or other combinations of inhaled, oral or intravenous antibiotics. We excluded non-randomised trials, cross-over trials, and those utilising historical controls. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed risk of bias and extracted data. MAIN RESULTS: The search identified 49 trials; seven trials (744 participants) with a duration between 28 days and 27 months were eligible for inclusion. Three of the trials are over 10 years old and their results may be less applicable today given the changes in standard treatment. Some of the trials had low numbers of participants and most had relatively short follow-up periods; however, there was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment given the interventions and comparators used. Two trials were supported by the manufacturers of the antibiotic used.Evidence from two trials (38 participants) at the two-month time-point showed treatment of early Pseudomonas aeruginosa infection with inhaled tobramycin results in microbiological eradication of the organism from respiratory secretions more often than placebo, odds ratio 0.15 (95% confidence interval 0.03 to 0.65) and data from one of these trials, with longer follow up, suggested that this effect may persist for up to 12 months.One randomised controlled trial (26 participants) compared oral ciprofloxacin and nebulised colistin versus usual treatment. Results after two years suggested treatment of early infection results in microbiological eradication of Pseudomonas aeruginosa more often than no anti-pseudomonal treatment, odds ratio 0.12 (95% confidence interval 0.02 to 0.79).One trial comparing 28 days to 56 days treatment with nebulised tobramycin solution for inhalation in 88 participants showed that both treatments were effective and well-tolerated, with no notable additional improvement with longer over shorter duration of therapy. However, this trial was not powered to detect non-inferiority or equivalence .A trial of oral ciprofloxacin with inhaled colistin versus nebulised tobramycin solution for inhalation alone (223 participants) failed to show a difference between the two strategies, although it was underpowered to show this. A further trial of inhaled colistin with oral ciprofloxacin versus nebulised tobramycin solution for inhalation with oral ciprofloxacin also showed no superiority of the former, with increased isolation of Stenotrophomonas maltophilia in both groups.A recent, large trial in 306 children aged between one and 12 years compared cycled nebulised tobramycin solution for inhalation to culture-based therapy and also ciprofloxacin to placebo. The primary analysis showed no difference in time to pulmonary exacerbation or proportion of Pseudomonas aeruginosa positive cultures. An analysis performed in this review (not adjusted for age) showed fewer participants in the cycled therapy group with one or more isolates of Pseudomonas aeruginosa, odds ratio 0.51 (95% CI 0.31 to 0.28). AUTHORS' CONCLUSIONS: We found that nebulised antibiotics, alone or in combination with oral antibiotics, were better than no treatment for early infection with Pseudomonas aeruginosa. Eradication may be sustained for up to two years. There is insufficient evidence to determine whether antibiotic strategies for the eradication of early Pseudomonas aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials of two active treatments have failed to show differences in rates of eradication of Pseudomonas aeruginosa. There have been no published randomised controlled trials that investigate the efficacy of intravenous antibiotics to eradicate Pseudomonas aeruginosa in cystic fibrosis. Overall, there is still insufficient evidence from this review to state which antibiotic strategy should be used for the eradication of early Pseudomonas aeruginosa infection in cystic fibrosis.

Rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome - neuro-endocrine tumours (ROHHAD-NET): case series and learning points.

OBJECTIVES: Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation (ROHHAD) is a rare syndrome associated with high morbidity and mortality. Diagnosis is often challenging. We describe three cases of ROHHAD with heterogeneous presentations but some consistent clinical features, including hyperprolactinaemia at diagnosis. We highlight when the diagnosis of ROHHAD should be considered at an early stage. CASE PRESENTATION: All three patients presented between 4 and 6 years old with rapid-onset obesity. They all have central hypoventilation requiring nocturnal BiPAP, varying degrees of hypothalamic dysfunction with hyperprolactinaemia being a consistent feature, and autonomic dysfunction. One patient has a neuro-endocrine tumour (NET) and two have glucose dysregulation. CONCLUSIONS: High prolactin was a consistent early feature. Central hypoventilation and NET may present later and therefore regular sleep studies and screening for NETs are required. A high suspicion of ROHHAD is warranted in patients with rapid, early-onset obesity and hyperprolactinaemia without structural pituitary abnormality.

Rituximab therapy in ROHHAD(NET) syndrome.

OBJECTIVES: Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation, and neural-crest tumour (ROHHAD(NET)) is a rare syndrome presenting in early childhood associated with high morbidity and mortality. There is no specific diagnostic biomarker and diagnosis is based on clinical features. An autoimmune origin has been postulated. CASE PRESENTATION: Management is largely supportive. We report a case of a five-year old female who presented in respiratory arrest after 6-months of rapid weight gain. She had central hypoventilation, central diabetes insipidus, growth hormone deficiency and hyperprolactinaemia. She displayed elevated interleukin-6 levels on cytokine serology which normalised after rituximab treatment. After rituximab treatment, her weight reduced significantly from greatly above the 99.6th to the 50th centile in 12 months. CONCLUSIONS: This response possibly reflects an underlying, immune-inflammatory pathology driving excess adiposity in this condition. Potentially, other aspects of ROHHAD(NET) may be mediated through autoimmune dysregulation in which case rituximab may provide benefits for prognosis and survival.

Management of pulmonary hypertension in Down syndrome.

UNLABELLED: Children with Down syndrome (DS) are at greater risk of pulmonary arterial hypertension (PAH) than the general population, partly due to upper airway obstruction and congenital heart disease. We wished to review our management of PAH and suggest a protocol for the systematic management of these children. Children with DS and PAH were included as referred for assessment from March 2005 to May 2010. Twenty-five patients (13 boys) met inclusion criteria. The median age was 385 days (range, 106 to 5,734); mean tricuspid regurgitation jet was 3.5 (range, 2.7-4.8) m/s. At cardiac catheterisation, mean pulmonary artery mean pressure was 26 mmHg (range, 12 to 46), and mean pulmonary vascular resistance (PVR) was 4.14 U.m² (range, 1.20 to 12.43) at baseline. PVR fell to a mean of 2.68 U.m² (range, 0.38 to 10.69) with 20 ppm inhaled nitric oxide and 100% oxygen. Respiratory assessment included polysomnography (18), bronchoscopy (16), showing malacia (eight), adenotonsillar hypertrophy (eight) and floppy aryepiglottic folds (four). One lung biopsy showed plexogenic arteriopathy, and one was diagnosed with tracheo-oesophageal fistula. CONCLUSION: In order to manage this complex group of patients, a combined cardiological, respiratory and surgical approach was required. A protocol with cardiac catheterisation, blood tests and respiratory assessment is suggested for the management of pulmonary hypertension in these children.

Increasing prevalence of domiciliary ventilation: changes in service demand and provision in the South West of the UK.

We examine the incidence and prevalence of domiciliary ventilation in the South West region of the UK, assess trends over 15 years, and describe patient outcome. We conducted a retrospective review of all patients below 18 years receiving domiciliary ventilation in the South West region of the UK between January 1994 and August 2009. Children who received long-term ventilation solely in hospital were excluded from the study. Information was obtained from a locally held database, medical notes, and hospital administration systems. One hundred-six patients were identified. Prevalence has increased since 1994 from 0.2 to 6.7 per 100,000 children. The incidence of both invasive and non-invasive ventilations has increased with a trend towards more non-invasive therapy. The commonest underlying disorders were airway pathology (37 patients), neuromuscular disease (34 patients), and central congenital hypoventilation disorder (17 patients). Sixty-seven patients had significant co-morbidities. Of 38 non-current patients, 19 were transferred to adult ventilation services, 11 died, and 6 were successfully weaned from ventilatory support. In conclusion, there has been a 30-fold increase in the prevalence of paediatric domiciliary ventilation, in the South West region of the UK, since 1994. Co-morbidities are common. Very few children discontinue long-term ventilation, and increasing numbers of ventilated children are transferred to adult services.

A breathless teenager.

In children with persistent chylothoraces of unknown origin, intranodal lymphangiography can be used to help identify the source of a leak. This may enable embolisation with glue and coils to enable resolution of the chylothoraces. https://bit.ly/3gskhgJ.

Intravenous or oral antibiotic treatment in adults and children with cystic fibrosis and Pseudomonas aeruginosa infection: the TORPEDO-CF RCT.

BACKGROUND: People with cystic fibrosis are susceptible to pulmonary infection with Pseudomonas aeruginosa. This may become chronic and lead to increased mortality and morbidity. If treatment is commenced promptly, infection may be eradicated through prolonged antibiotic treatment. OBJECTIVE: To compare the clinical effectiveness, cost-effectiveness and safety of two eradication regimens. DESIGN: This was a Phase IV, multicentre, parallel-group, randomised controlled trial. SETTING: Seventy UK and two Italian cystic fibrosis centres. PARTICIPANTS: Participants were individuals with cystic fibrosis aged > 28 days old who had never had a P. aeruginosa infection or who had been infection free for 1 year. INTERVENTIONS: Fourteen days of intravenous ceftazidime and tobramycin or 3 months of oral ciprofloxacin. Inhaled colistimethate sodium was included in both regimens over 3 months. Consenting patients were randomly allocated to either treatment arm in a 1 : 1 ratio using simple block randomisation with random variable block length. MAIN OUTCOME MEASURES: The primary outcome was eradication of P. aeruginosa at 3 months and remaining free of infection to 15 months. Secondary outcomes included time to reoccurrence, spirometry, anthropometrics, pulmonary exacerbations and hospitalisations. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who had received at least one dose of any of the study drugs. Cost-effectiveness analysis explored the cost per successful eradication and the cost per quality-adjusted life-year. RESULTS: Between 5 October 2010 and 27 January 2017, 286 patients were randomised: 137 patients to intravenous antibiotics and 149 patients to oral antibiotics. The numbers of participants achieving the primary outcome were 55 out of 125 (44%) in the intravenous group and 68 out of 130 (52%) in the oral group. Participants randomised to the intravenous group were less likely to achieve the primary outcome; although the difference between groups was not statistically significant, the clinically important difference that the trial aimed to detect was not contained within the confidence interval (relative risk 0.84, 95% confidence interval 0.65 to 1.09; p = 0.184). Significantly fewer patients in the intravenous group (40/129, 31%) than in the oral group (61/136, 44.9%) were hospitalised in the 12 months following eradication treatment (relative risk 0.69, 95% confidence interval 0.5 to 0.95; p = 0.02). There were no clinically important differences in other secondary outcomes. There were 32 serious adverse events in 24 participants [intravenous: 10/126 (7.9%); oral: 14/146 (9.6%)]. Oral therapy led to reductions in costs compared with intravenous therapy (-£5938.50, 95% confidence interval -£7190.30 to -£4686.70). Intravenous therapy usually necessitated hospital admission, which accounted for a large part of this cost. LIMITATIONS: Only 15 out of the 286 participants recruited were adults - partly because of the smaller number of adult centres participating in the trial. The possibility that the trial participants may be different from the rest of the cystic fibrosis population and may have had a better clinical status, and so be more likely to agree to the uncertainty of trial participation, cannot be ruled out. CONCLUSIONS: Intravenous antibiotics did not achieve sustained eradication of P. aeruginosa in a greater proportion of cystic fibrosis patients. Although there were fewer hospitalisations in the intravenous group during follow-up, this confers no advantage over the oral therapy group, as intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P. aeruginosa in cystic fibrosis. FUTURE WORK: Future research studies should combine long-term follow-up with regimens to reduce reoccurrence after eradication. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02734162 and EudraCT 2009-012575-10. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 65. See the NIHR Journals Library website for further project information.

Cystic fibrosis is a genetic condition that affects mucous glands, causing sticky mucus in the lungs and digestive system. People with cystic fibrosis are prone to lung infection with a bacterium called Pseudomonas aeruginosa, which can lead to serious long-term complications and death. It is possible to eradicate P. aeruginosa if antibiotics are started promptly and taken for several months. The Trial of Optimal TheRapy for Pseudomonas EraDicatiOn in Cystic Fibrosis (TORPEDO-CF) was designed to find out if intravenous ceftazidime and tobramycin were better at eradicating P. aeruginosa than oral ciprofloxacin. A total of 286 children, young people and adults with cystic fibrosis joined the study from 70 UK and two Italian centres. Approximately half of the participants received treatment with intravenous antibiotics and half with oral antibiotics. All participants received inhaled colistin for 3 months and were followed up for a minimum of 15 months. We studied whether or not either treatment eradicated P. aeruginosa, and if reinfection happened during follow-up. We also collected data on lung function, other chest infections and hospital admissions, and examined whether or not one treatment was more cost-effective than the other. In total, 15 adults joined TORPEDO-CF, so the study population may not totally match the wider cystic fibrosis population; however, in TORPEDO-CF, we found that intravenous antibiotics did not achieve persistent eradication of P. aeruginosa in a greater proportion of cystic fibrosis patients. We also found that oral antibiotics were more cost-effective than intravenous antibiotics. The intravenous antibiotics group had fewer hospital admissions during follow-up, but, as they were usually admitted for their initial treatment, this was not considered an advantage over the oral antibiotics group. The TORPEDO-CF results do not support the use of intravenous antibiotics to eradicate P. aeruginosa in cystic fibrosis and, when the findings of this trial are applied in routine clinical practice in the NHS, patients will most likely receive oral treatment as an outpatient, avoiding the need for hospital admission.

A novel de novo ACTA1 variant in a patient with nemaline myopathy and mitochondrial Complex I deficiency.

We describe the presentation and follow-up of a three-year-old girl with nemaline myopathy due to a de-novo variant in ACTA1 (encoding skeletal alpha actin) and moderately low enzyme level of Complex I of the mitochondrial respiratory chain. She presented in the neonatal period with hypotonia, followed by weakness in the facial, bulbar, respiratory and neck flexors muscles. A biopsy of her quadriceps muscle at the age of one year showed nemaline rods. Based on her clinical presentation of a congenital myopathy and histopathological features on a muscle biopsy, ACTA1 was sequenced, and this revealed a novel sequence variant, c.760 A>C p. (Asn254His). In addition, mitochondrial respiratory chain enzymatic activity of skeletal muscle biopsy showed a moderately low activity of complex I (nicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase). Disturbances of Complex I of the respiratory chain have been reported in patients with nemaline myopathy, although the mechanism remains unclear.

Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis.

BACKGROUND: Lower respiratory tract infection with Pseudomonas aeruginosa occurs in most people with cystic fibrosis (CF). Once chronic infection is established, Pseudomonas aeruginosa is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate. OBJECTIVES: To determine whether antibiotic treatment of early Pseudomonas aeruginosa infection in children and adults with CF eradicates the organism, improves clinical and microbiological outcome and is superior to or more cost-effective than other strategies. SEARCH STRATEGY: We searched the Cochrane CF and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 11 December 2008. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people with CF, in whom Pseudomonas aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous antibiotics with placebo, usual treatment or other combinations of inhaled, oral or intravenous antibiotics. We excluded non-randomised trials, cross-over trials, and those utilising historical controls. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed methodological quality and extracted data. MAIN RESULTS: The search identified 25 trials. Four trials (95 participants) were eligible for inclusion; two trials are ongoing. Evidence from two trials showed treatment of early Pseudomonas aeruginosa infection with inhaled tobramycin results in microbiological eradication of the organism from respiratory secretions more often than placebo, OR 0.15 (95% CI 0.03 to 0.65) and that this effect may persist for up to 12 months. These trials were of low methodological quality.The only identified RCT of oral ciprofloxacin and nebulised colistin versus usual treatment was of poor methodological quality. Results suggested treatment of early infection results in microbiological eradication of Pseudomonas aeruginosa more often than usual treatment, after two years, OR 0.24 (95% CI 0.06 to 0.96). There is insufficient evidence to determine whether antibiotic strategies for the eradication of early Pseudomonas aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. AUTHORS' CONCLUSIONS: We found that nebulised antibiotics, alone or in combination with oral antibiotics, were better than no treatment for early infection with Pseudomonas aeruginosa. Eradication may be sustained in the short term. Overall, there is insufficient evidence from this review to state which antibiotic strategy should be used for the eradication of early Pseudomonas aeruginosa infection in CF.

Influence of tracheobronchomalacia on outcome of surgery in children with congenital heart disease and its management.

BACKGROUND: Patients with complex congenital heart disease associated with tracheobronchomalacia (TBM) remain difficult to manage after cardiac surgery. We studied the influence of TBM on the outcomes of pediatric patients after cardiac surgery for congenital heart disease to determine how to manage these patients better. METHODS: Twenty-two consecutive pediatric patients who had TBM diagnosed by bronchoscopy or dynamic contrast bronchography before or after cardiac surgery for congenital heart disease during a 5.5-year period were compared with an age- and procedure-matched control group operated on during the same period. Patients diagnosed postoperatively were investigated after a second failed extubation. Patients were managed by oxygen administration, endotracheal suctioning, and positive end-expiratory or continuous positive airway pressure through a nasotracheal tube or tracheostomy. RESULTS: There were 4 deaths within 1 year of surgery, all in the study group, with 2 early (neither of which appeared related to TBM) and 2 late. The estimated survival at 5 years was 82% (95% confidence interval, 59% to 93%) for the study group compared with 100% for control patients (p = 0.012). All deaths occurred in patients undergoing palliative procedures (p = 0.0004), and both children who underwent redo operations died (p = 0.02). Postoperatively, 50% of children with TBM required prolonged ventilation and tracheostomy. Compared with control patients the average postoperative ventilation time, pediatric intensive care unit stay, and hospital stay were 6.5, 11.5, and 20 days versus 1, 2, and 6.5 days, respectively (p < 0.001). CONCLUSIONS: Although associated with longer postoperative ventilation time, pediatric intensive care unit stay, hospital stay, and mortality, outcomes after cardiac procedures in children with TBM are acceptable. Palliative and redo procedures in this group of patients are associated with significantly higher risk of death.

Altered phospholipid composition and aggregate structure of lung surfactant is associated with impaired lung function in young children with respiratory infections.

Alterations to pulmonary surfactant structure, composition, and function contribute to the severity of respiratory infections. Analysis of bronchoalveolar lavage fluid (BALF) from children undergoing diagnostic bronchoscopy for structural abnormalities (control group, n = 24), asthma (n = 18), lung infection (n = 30), and cystic fibrosis (CF, n = 15) showed that BALF phospholipid concentration decreased with age for the control group and was elevated in all disease groups. The fractional concentration of the major surface active component, dipalmitoyl phosphatidylcholine (PC16:0/16:0), correlated (r(2) = 0.608, P < 0.01) with airway resistance (FEV(1%) predicted), and decreased PC16:0/16:0 was accompanied by increased concentrations of phospholipid components characteristic of cell membranes (PC16:0/18:1 and PI18:0/20:4). Median minimal surface tension, measured by pulsating bubble surfactometer, was elevated (P < 0.01) in both infection (17.5 mN/m) and CF (17.1 mN/m) compared with the control group (1.5 mN/m). Centrifugation (60,000 x g, 40 min) of BALF indicated that infection was accompanied by accumulation of large aggregate forms of surfactant, in contrast to previous reports of increased conversion to inactive small aggregate surfactant particles in ventilated patients with respiratory failure. This accumulation of surface-inactive, large aggregate forms of surfactant, possibly due to mixing with membrane material from inflammatory cells, may contribute to severity of lung disease in children with respiratory infections.