Changes in liver biochemistry and tacrolimus levels following the introduction of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and liver transplant.

INTRODUCTION: Elevated liver function tests (LFTs) are reported in individuals with cystic fibrosis (CF) starting elexacaftor/tezacaftor/ivacaftor (ETI). We report our experience with ETI in CF liver transplant patients. METHOD: All CF liver transplant patients under the care of the Leeds CF team were commenced on ETI. Liver biopsies were performed when ALT >3 times upper limit of normal with or without bilirubin elevation. Treatment was guided by transplant hepatology and CF teams. Clinical data including lung function, LFTs and tacrolimus levels were collected. RESULTS: Four patients (3 male, 1 female) on tacrolimus were commenced on ETI. Median time post liver transplantation was 6.5 years. Three patients underwent liver biopsy. One biopsy was abnormal with immune-mediated liver injury, which responded to increased immunosuppression. Management of tacrolimus levels proved straightforward. CONCLUSION: ETI therapy in CF post liver transplant recipients was encouraging. Normal liver biopsy provides re-assurance to continue treatment despite elevated LFTs.

Dose adjustments of Elexacaftor/Tezacaftor/Ivacaftor in response to mental health side effects in adults with cystic fibrosis.

INTRODUCTION: Deterioration in mental health has been reported in a minority of individuals with cystic fibrosis starting elexacafor/tezacaftor/ivacaftor (ELX/TEZ/IVA). We report our experience of using sweat chloride and markers of clinical stability to titrate dose reduction with the aim of minimising adverse events and maintaining clinical stability. METHOD: Adults (n = 266) prescribed ELX/TEZ/IVA, were included. Adverse events, sweat chloride, lung function and clinical data were collected. RESULTS: Nineteen (7.1%) individuals reported anxiety, low mood, insomnia and "brain fog" with reduced attention and concentration span. Thirteen underwent dose reduction with sweat chloride remained normal (<30 mmol l-1) or borderline (30-60 mmol l-1) in six (46.2%) and seven (53.2%) cases respectively. Improvement or resolution of AEs occurring in 10 of the 13 cases. CONCLUSION: Dose adjustment of ELX/TEZ/IVA was associated with improvement in mental health AEs without significant clinical deterioration. Sweat chloride concentration may prove useful as a surrogate marker of CFTR function.

Why is mock care not a good proxy for predicting hand contamination during patient care?

BACKGROUND: Healthcare worker (HCW) behaviours, such as the sequence of their contacts with surfaces and hand hygiene moments, are important for understanding disease transmission. AIM: To propose a method for recording sequences of HCW behaviours during mock vs actual procedures, and to evaluate differences for use in infection risk modelling and staff training. METHODS: Procedures for three types of care were observed under mock and actual settings: intravenous (IV) drip care, observational care and doctors' rounds on a respiratory ward in a university teaching hospital. Contacts and hand hygiene behaviours were recorded in real-time using either a handheld tablet or video cameras. FINDINGS: Actual patient care demonstrated 70% more surface contacts than mock care. It was also 2.4 min longer than mock care, but equal in terms of patient contacts. On average, doctors' rounds took 7.5 min (2.5 min for mock care), whilst auxiliary nurses took 4.9 min for observational care (2.4 min for mock care). Registered nurses took 3.2 min for mock IV care and 3.8 min for actual IV care; this translated into a 44% increase in contacts. In 51% of actual care episodes and 37% of mock care episodes, hand hygiene was performed before patient contact; in comparison, 15% of staff delivering actual care performed hand hygiene after patient contact on leaving the room vs 22% for mock care. The number of overall touches in the patient room was a modest predictor of hand hygiene. Using a model to predict hand contamination from surface contacts for Staphylococcus aureus, Escherichia coli and norovirus, mock care underestimated micro-organisms on hands by approximately 30%.

Use of ceftazidime/avibactam for the treatment of MDR Pseudomonas aeruginosa and Burkholderia cepacia complex infections in cystic fibrosis: a case series.

BACKGROUND: The efficacy of antibiotic treatment in pulmonary and systemic infections in cystic fibrosis (CF) is limited by the increased prevalence of MDR strains of Pseudomonas aeruginosa and Burkholderia cepacia complex. Ceftazidime/avibactam is a new combination which, in vitro, appears to have good activity against MDR strains of P. aeruginosa and B. cepacia complex. METHODS: A retrospective analysis was performed including adult patients with CF who received at least one course of ceftazidime/avibactam owing to pulmonary exacerbations not responding to conventional antibiotic treatment. RESULTS: Treatment with ceftazidime/avibactam was associated with reduction in inflammatory markers and improvement in lung function. No episodes of acute kidney injury or elevation in transaminase were observed. CONCLUSIONS: Ceftazidime/avibactam appeared to be well tolerated and improved patients' outcomes. Further studies are needed to better assess the role of this new combination in CF.

Intravenous fosfomycin for pulmonary exacerbation of cystic fibrosis: Real life experience of a large adult CF centre.

BACKGROUND: The increased prevalence of multi-drug resistant strains of P.aeruginosa and allergic reactions among adult patients with cystic fibrosis (CF) limits the number of antibiotics available to treat pulmonary exacerbations. Fosfomycin, a unique broad spectrum bactericidal antibiotic, might offer an alternative therapeutic option in such cases. AIM: To describe the clinical efficacy, safety and tolerability of intravenous fosfomycin in combination with a second anti-pseudomonal antibiotic to treat pulmonary exacerbations in adult patients with CF. METHOD: A retrospective analysis of data captured prospectively, over a 2-years period, on the Unit electronic medical records for patients who received IV fosfomycin was performed. Baseline characteristics in the 12 months prior treatment, lung function, CRP, renal and liver function and electrolytes at start and end of treatment were retrieved. RESULTS: 54 patients received 128 courses of IV fosfomycin in combination with a second antibiotic, resulting in improved FEV1 (0.94 L vs 1.24 L, p < 0.01) and reduced CRP (65 mg/L vs 19.3 mg/L, p < 0.01). Renal function pre- and post-treatment remained stable. 4% (n = 5) of courses were complicated with AKI at mid treatment, which resolved at the end of the course. Electrolyte supplementation was required in 18% of cases for potassium and magnesium and 7% for phosphate. Nausea was the most common side effect (48%), but was well controlled with anti-emetics. CONCLUSION: Antibiotic regimens including fosfomycin appear to be clinically effective and safe. Fosfomycin should, therefore, be considered as an add-on therapy in patients who failed to respond to initial treatment and with multiple drug allergies.

Omalizumab for the treatment of severe persistent allergic asthma: a systematic review and economic evaluation.

BACKGROUND: Allergic asthma is a long-term disorder of the airways resulting from overexpression of immunoglobulin E (IgE) in response to environmental allergens. Patients with poorly controlled asthma are at high risk of exacerbations requiring additional treatment, including hospitalisations. Severe exacerbations are potentially life threatening. Guidelines identify five treatment steps for both adults and children. Omalizumab (Xolair(®)) is a recombinant DNA-derived humanised monoclonal antibody indicated as an add-on therapy in patients aged ≥ 6 years with severe persistent allergic asthma uncontrolled at treatment step 4 or 5. OBJECTIVE: To determine the clinical effectiveness, safety and cost-effectiveness of omalizumab, as an add-on therapy to standard care, within its licensed indication, compared with standard therapy alone for the treatment of severe persistent allergic asthma in adults and adolescents aged ≥ 12 years and children aged 6-11 years. DATA SOURCES: Eleven electronic databases (including MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials) and additional sources including regulatory agency reports were searched from inception to October 2011. Additional data sources include: the manufacturer's submission (MS); two previous National Institute for Health and Care Excellence (NICE) single technology appraisal (STA) submissions; and existing reviews on the safety of omalizumab and oral corticosteroids (OCSs). REVIEW METHODS: Systematic reviews of the clinical effectiveness and cost-effectiveness evidence for omalizumab were performed. The primary outcome was number of clinically significant (CS) exacerbations. Other outcomes included asthma symptoms, unscheduled health-care use, asthma-related mortality, OCS use and health-related quality of life (HRQoL). Because of methodological and clinical heterogeneity between trials, a narrative synthesis was applied. Pragmatic reviews with best evidence syntheses were used to assess adverse events of omalizumab and OCSs. The cost-effectiveness of omalizumab was assessed from the perspective of the UK NHS in the two separate populations: adults and adolescents, and children, using a cohort Markov model. Costs and outcomes were discounted at 3.5% per annum. Results are presented for additional subgroup populations: (1) hospitalised for asthma in the previous year, (2) adults and adolescents on maintenance OCSs and (3) three or more exacerbations in the previous year. RESULTS: Eleven randomised controlled trials (RCTs) and 13 observational studies were identified, including four RCTs/subgroups in the adult licensed population and one subgroup in children. A minority of patients were on maintenance OCSs. No evidence comparing omalizumab with OCSs was identified. Omalizumab significantly reduced the incidence of CS exacerbations in both adults and children [adults: INvestigatioN of Omalizumab in seVere Asthma Trial (INNOVATE): rate ratio 0.74; 95% CI 0.55 to 1.00; children IA-05 EUP (the a priori subgroup of patients who met the European Medicines Agency license criteria) 0.66; 95% CI 0.44 to 1.00]. Significant benefits were observed for a range of other outcomes in adults. Subgroup evidence showed benefits in adults on maintenance OCSs. Evidence for an OCS-sparing effect of omalizumab was limited but consistent. Omalizumab is available as 75 mg and 150 mg prefilled syringes at prices of £128.07 and £256.15 respectively. The incremental cost-effectiveness ratio (ICER) for adults and adolescents is £83,822 per quality-adjusted life-year (QALY) gained, whereas the ICER for children is £78,009 per QALY gained. The results are similar for the subgroup population of ≥ 3 exacerbations in the previous year, whereas the ICER for the other subgroup populations are lower; £46,431 for the hospitalisation subgroup in adults and adolescents, £44,142 for the hospitalisation subgroup in children and £50,181 for the maintenance OCS subgroup. CONCLUSION: Omalizumab reduces the incidence of CS exacerbations in adults and children, with benefits on other outcomes in adults. Limited, underpowered subgroup evidence exists that omalizumab reduces exacerbations and OCS requirements in adults on OCSs. Evidence in children is weaker and more uncertain. The ICERs are above conventional NHS thresholds of cost-effectiveness. The key drivers of cost-effectiveness are asthma-related mortality risk and, to a lesser extent, HRQoL improvement and OCS-related adverse effects. An adequately powered double-blind RCT in both adults and children on maintenance OCSs and an individual patient data meta-analysis of existing trials should be considered. A registry of all patients on omalizumab should be established. STUDY REGISTRATION: The study was registered as PROSPERO CRD42011001625. FUNDING: This report was commissioned by the National Institute for Health Research Health Technology Assessment programme on behalf of NICE as project number HTA 10/128/01.

Cytomegalovirus pneumonia in an immunocompetent adult: a case report.

A 38 year-old woman, who was previously fit and well, presented with a 10 day history of fever and non-specific symptoms. Initial chest X-ray demonstrated patchy nodular infiltrates bilaterally. She became increasingly hypoxaemic. Cultures to this point were all negative. A high-resolution CT thorax showed diffuse multilobular ground glass appearance with peripheral nodular shadowing, consistent with a viral pneumonia. CMV IgM antibody was positive and CMV PCR was positive on two subsequent occasions. She was commenced on oral valganciclovir. She made a full recovery and was discharged seven days later.

The Effect of Sub-MIC ß-Lactam Antibiotic Exposure of Pseudomonas aeruginosa Strains from People with Cystic Fibrosis in a Desiccation Survival Model.

Prior to modern typing methods, cross-infection of P. aeruginosa between people with cystic fibrosis (CF) was felt to be rare. Recently a number of studies have demonstrated the presence of clonal strains of P. aeruginosa infecting people with CF. The aim of this study was to determine whether strains of P. aeruginosa demonstrated differences in resistance to desiccation and whether preincubation in subminimum inhibitory concentrations (MICs) of ß-lactam affected desiccation resistance. The experimental data were modelled to a first-order decay model and a Weibull decay model using least squares nonlinear regression. The Weibull model was the preferred model for the desiccation survival. The presence of a mucoid phenotype promoted desiccation survival. Preincubation with antibiotics did not have a consistent effect on the strains of P. aeruginosa. Meropenem reduced desiccation resistance, whereas ceftazidime had much less effect on the strains studied.

An aerobiological model of aerosol survival of different strains of Pseudomonas aeruginosa isolated from people with cystic fibrosis.

Pseudomonas aeruginosa is a common and important pathogen in people with cystic fibrosis (CF). Recently epidemic strains of P. aeruginosa associated with increased morbidity, have been identified. The method of transmission is not clear, but there is evidence of a potential airborne route. The aim of this study was to determine whether different strains of P. aeruginosa isolated from people with CF were able to survive within artificially generated aerosols in an aerobiological chamber. Viable P. aeruginosa could still be detected up to 45min after halting generation of the aerosols. All of the strains of P. aeruginosa expressing a non-mucoid phenotype isolated from people with CF had a reduced ability to survive within aerosols compared to an environmental strain. Expression of a mucoid phenotype by the strains of P. aeruginosa isolated from people with CF promoted survival in the aerosol model compared to strains expressing a non-mucoid phenotype.

Acute Burkholderia cenocepacia pyomyositis in a patient with cystic fibrosis.

INTRODUCTION: Extra-pulmonary complications of Burkholderia cepacia complex (Bcc) infection in patients with cystic fibrosis are unusual. To the best of the authors' knowledge no case of pyomyositis secondary to Bcc infection has been reported previously. CASE PRESENTATION: We report a case of pyomyositis of the forearm caused by Bcc infection in a patient with CF. We also briefly discuss the management of pyomyositis. CONCLUSION: Pyomyositis is a potential extra-pulmonary complication of Bcc infection in patients with CF. A high index of clinical suspicion is required to make a prompt diagnosis. Final diagnosis may need MRI. An early diagnosis, aggressive medical therapy, multidisciplinary care and timely surgical intervention are all essential for proper management of this condition.

Nutritional decline in cystic fibrosis related diabetes: the effect of intensive nutritional intervention.

BACKGROUND: Reports indicate that nutritional and respiratory decline occur up to four years prior to diagnosis of cystic fibrosis related diabetes (CFRD). Our aim was to establish whether intensive nutritional intervention prevents pre-diabetic nutritional decline in an adult population with CFRD. METHODS: 48 adult patients with CFRD were matched to 48 controls with CF, for age, gender and lung pathogen status. Nutritional and other clinical indices were recorded at annual intervals from six years before until two years after diagnosis. Data were also analysed to examine the impact of early and late acquisition of CFRD. RESULTS: No important differences in weight, height, body mass index (BMI), lung function or intravenous treatment were found between groups in the six years prior to diagnosis, nor any significant deviation over time. In those who developed diabetes, use of overnight enteral tube feeding (ETF) was four times as likely at the time of diagnosis, compared to controls [ETF 43.8% (CFRD) v 18.8% (CF Controls), OR 4.0, CI 1.3 to 16.4, p=0.01]. Age at onset of CFRD played a significant role in determining the pre-diabetic clinical course. Younger diabetics with continued growth at study onset (n=17) had a lower BMI from 2 years prior to diagnosis compared to controls [BMI 18.9 kg/m(2) (CFRD) v 20.8 kg/m(2) (CF Controls), diff=1.9, CI -0.1 to 3.7 p=0.04]. The BMI of older diabetics (completed growth at study onset) was equal to that of controls throughout. CONCLUSION: Pre-diabetic nutritional decline is not inevitable in adults with CFRD, but is influenced by age of onset. In the group overall, those with CFRD are more likely to require ETF from 2 years prior to diagnosis. Despite intensive nutritional intervention, patients who continue to grow throughout the pre-diabetic years, show a level of nutritional decline absent in older adults.

Mechanisms and structures of crotonase superfamily enzymes--how nature controls enolate and oxyanion reactivity.

Structural and mechanistic studies on the crotonase superfamily (CS) are reviewed with the aim of illustrating how a conserved structural platform can enable catalysis of a very wide range of reactions. Many CS reactions have precedent in the 'carbonyl' chemistry of organic synthesis; they include alkene hydration/isomerization, aryl-halide dehalogenation, (de)carboxylation, CoA ester and peptide hydrolysis, fragmentation of beta-diketones and C-C bond formation, cleavage and oxidation. CS enzymes possess a canonical fold formed from repeated betabetaalpha units that assemble into two approximately perpendicular beta-sheets surrounded by alpha-helices. CS enzymes often, although not exclusively, oligomerize as trimers or dimers of trimers. Two conserved backbone NH groups in CS active sites form an oxyanion 'hole' that can stabilize enolate/oxyanion intermediates. The range and efficiency of known CS-catalyzed reactions coupled to their common structural platforms suggest that CS variants may have widespread utility in biocatalysis.

Ten years of viral and non-bacterial serology in adults with cystic fibrosis.

Viral infections are associated with pulmonary exacerbations in children with cystic fibrosis (CF), but few studies have addressed the frequency in adults. This paper investigates the frequency and impact of viral infections in adults with CF receiving intravenous antibiotics. Pre- and post-treatment spirometry, inflammatory markers and antibody titres against influenza A, influenza B, adenovirus, respiratory syncytial virus, Mycoplasma pneumoniae, Chlamydia psittaci, and Coxiella burnetti were analysed over a 10-year period. Non-bacterial infections were identified in 5.1% of 3156 courses of treatment. The annual incidence of admissions per patient associated with viral infection was 4.9%. The presence of viral infection in association with a pulmonary exacerbation did not adversely affect lung function or inflammatory markers in the short term. Adults with CF have a lower incidence of respiratory viral infections associated with pulmonary exacerbations requiring intravenous antibiotics compared to children and infants with CF.

Measurement of urinary N-acetyl-b-D-glucosaminidase in adult patients with cystic fibrosis: before, during and after treatment with intravenous antibiotics.

BACKGROUND: Patients with cystic fibrosis (CF) are at high risk from the nephrotoxic effects of intravenous antibiotics due to repeated and prolonged courses of therapy. Routine methods of monitoring renal injury are insensitive. N-acetyl-b-d-glucosaminidase (NAG) is a lysosomal enzyme present in the renal proximal tubular cells, with increased excretion an indicator of renal tubular dysfunction. METHODS: Urinary NAG, creatinine, serum creatinine, electrolytes and BUN were measured on days 1, 14 and at the first out-patient visit following treatment with tobramycin or colistin. Urinary NAG levels were corrected for urinary creatinine and expressed as a NAG ratio. Patients who received>1 course of intravenous antibiotics during the study period were included in a separate analysis of the cumulative effect of treatment. RESULTS: 88 patients (44 female, 31 with CFRD) completed a single course of intravenous antibiotics. 71 patients had urinary NAG levels at follow-up. The median time to follow-up was 50 days. Serum electrolytes, creatinine and BUN were normal throughout. A 3.5-fold increase in urinary NAG excretion was observed between day 1 and 14 and 46% of patients had an elevated NAG level at follow-up. A highly significant difference in NAG excretion was observed on day 14 for tobramycin vs. colistin (median 2.24 vs. 0.98, p<0.001). A significant difference in NAG excretion was seen in patients with CFRD at all measured time points. Patients with CFRD had a significantly worse clinical status and had received more days of intravenous antibiotics over the previous 6 years. In 20 (80%) of 25 patients who received>1 course of treatment during the study period, baseline NAG levels were significantly higher in subsequent courses (p<0.001). There was a significant correlation between previous exposure to colistin and baseline NAG levels (r=0.389, p<0.001). CONCLUSIONS: Both tobramycin and colistin cause acute renal tubular injury with a significant rise in urinary NAG excretion. Patients with CFRD seem to be at greatest risk of renal tubular damage. Cumulative damage is evident with repeated dosing. Previous exposure to nephrotoxic antibiotics, especially colistin, is associated with elevated baseline NAG levels. We recommend that colistin is reserved for patients with resistant Pseudomonas aeruginosa or those who are intolerant to tobramycin. Serial longitudinal NAG measurements may be useful in patients with CF, especially those with CFRD, to identify patients at risk of developing renal disease.

The treatment of spinal tuberculosis: a retrospective study.

BACKGROUND: There are conflicting guidelines and variations in clinical practice in the management of bone tuberculosis (TB), including spinal TB. A case who received 6 months of treatment in line with current British Thoracic Society (BTS) guidelines, and subsequently relapsed, prompted a survey of treatment and outcomes of spinal and other bone TB. METHODS: A retrospective study examining the clinical features, treatment duration and outcome of patients presenting with spinal and other bone TB to the Leeds Teaching Hospitals National Health Service Trust, between 1998 and 2002. RESULTS: Forty-two patients were identified. Notes from 34 patients with spinal TB and four patients with TB of other bones were reviewed. Of eight patients who received 6 months of therapy, five relapsed. Of 30 patients who received treatment for 9 months or longer, none relapsed (P < 0.05). CONCLUSION: Six months of treatment, as currently recommended by the BTS, may be inadequate for bone TB, including spinal TB.

Treatment of resistant distal intestinal obstruction syndrome with a modified antegrade continence enema procedure.

We report a case of a patient with CF who had a long history of recurrent distal intestinal obstruction syndrome. She had been treated with conventional treatment including gastrografin, n-acetyl cysteine, Klean prep and Picolax. She underwent a modified antegrade continence enema procedure. She currently irrigates her conduit every 2-3 days. She has had no further symptoms of distal intestinal obstruction syndrome.

Structure of proline 3-hydroxylase. Evolution of the family of 2-oxoglutarate dependent oxygenases.

Iron (II)/2-oxoglutarate (2-OG)-dependent oxygenases catalyse oxidative reactions in a range of metabolic processes including the hydroxylation of proline and lysine residues during the post-translational modification of collagen. 2-OG oxygenases commonly require ascorbate for full activity. In the vitamin C deficient disease, scurvy, reduced activity of 2-OG oxygenases results in impaired formation of collagen. Here we report the crystal structure of bacterial proline 3-hydroxylase from Streptomyces sp., an enzyme which hydroxylates proline at position 3, the first of a 2-OG oxygenase catalysing oxidation of a free alpha-amino acid. Structures were obtained for the enzyme in the absence of iron (to 2.3A resolution, R=20.2%, Rfree=25.3%) and that complexed to iron (II) (to 2.4A resolution, R=19.8%, Rfree=22.6%). The structure contains conserved motifs present in other 2-OG oxygenases including a 'jelly roll' beta strand core and residues binding iron and 2-oxoglutarate, consistent with divergent evolution within the extended family. The structure differs significantly from many other 2-OG oxygenases in possessing a discrete C-terminal helical domain. Analysis of the structure suggests a model for proline binding and a mechanism for uncoupling of proline and 2-OG turnover.

Structure-function analysis of phytanoyl-CoA 2-hydroxylase mutations causing Refsum's disease.

Refsum's disease is a neurological syndrome characterized by adult-onset retinitis pigmentosa, anosmia, sensory neuropathy and phytanic acidaemia. Many cases are caused by mutations in peroxisomal oxygenase phytanoyl-CoA 2-hydroxylase (PAHX) which catalyses the initial alpha-oxidation step in the degradation of phytanic acid. Both pro and mature forms of recombinant PAHX were produced in Escherichia coli, highly purified, and shown to have a requirement for iron(II) as a co-factor and 2-oxoglutarate as a co-substrate. Sequence analysis in the light of crystallographic data for other members of the 2-oxoglutarate-dependent oxygenase super-family led to secondary structural predictions for PAHX, which were tested by site-directed mutagenesis. The H175A and D177A mutants did not catalyse hydroxylation of phytanoyl-CoA, consistent with their assigned role as iron(II) binding ligands. The clinically observed P29S, Q176K, G204S, N269H, R275Q and R275W mutants were assayed for both 2-oxoglutarate and phytanoyl-CoA oxidation. The P29S mutant was fully active, implying that the mutation resulted in defective targeting of the protein to peroxisomes. Mutation of Arg-275 resulted in impaired 2-oxoglutarate binding. The Q176K, G204S and N269H mutations caused partial uncoupling of 2-oxoglutarate conversion from phytanoyl-CoA oxidation. The results demonstrate that the diagnosis of Refsum's disease should not solely rely upon PAHX assays for 2-oxoglutarate or phytanoyl-CoA oxidation.