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Abstract Background: Pseudomonas aeruginosa (Pa) is the predominant pathogen infecting the airways of patients with cystic fibrosis (CF). Initial colonization is usually transient and associated with non-mucoid strains, which can be eradicated if identified early. This strategy can prevent, or at least delay, chronic Pa infection, which eventually develops in the majority of patients by their late teens or early adulthood. This article discusses the management and latest treatment developments of Pa lung infection in patients with CF, with a focus on nebulized antibiotic therapy. Methods: PubMed was searched to identify English language articles published up until August 2011 using combinations of the following key words: 'antibiotics', 'chronic', 'cystic fibrosis', 'eradication', 'exacerbations', 'guidelines', 'inhaled', 'intravenous', 'lung infection', 'burden', 'adherence', 'patient segregation', 'pseudomonas aeruginosa' and 'resistance'. Findings: Antibiotics form a central part of the treatment regimens for chronic Pa lung infection. Current treatment guidelines recommend that patients with chronic pulmonary infection with Pa should receive long-term inhaled anti-pseudomonal therapy to preserve lung function, and to reduce the frequency of pulmonary exacerbations and hospital admissions. While antibiotic resistance seems to increase with frequent antibiotic use, this does not appear to impact on clinical outcome. Negative aspects of therapy include the time needed for drug administration and subsequent cleaning of the equipment. These factors cause a significant treatment burden and impact on adherence. The availability of more convenient formulations and delivery vehicles for anti-pseudomonal antibiotics may help overcome some of these challenges. Conclusions: Current challenges in the management of CF patients with chronic Pa lung infection are numerous. The availability of novel anti-pseudomonal antibiotic formulations/devices is anticipated to improve treatment adherence in patients with CF, and could improve clinical outcomes. Thus, there is hope for improved survival in individuals with CF suffering from chronic pulmonary infection with Pa. [ABSTRACT FROM AUTHOR]

Abstract: Non-immediate hypersensitivity reactions to antibiotics in patients with CF represent a real-life challenge for clinicians. Desensitization is often performed in patients who have exhausted all therapeutic options. Whilst desensitization is an established procedure for immediate reactions we assessed the outcomes and safety of desensitization for non-immediate reactions. We retrospectively reviewed 275 desensitization procedures in 42 patients with a range of non-immediate reactions to six commonly used antibiotics. Desensitization was performed using a 7-step rapid intravenous protocol on a normal medical ward. 250 (91%) of overall desensitization procedures were successful; however, this figure incorporates certain individuals having multiple successful procedures. Individual patient success ranged from 55% with tazocin through to 88% with tobramycin. In the 25 patients who failed desensitization the reactions were mild and the majority occurred within 48h of starting treatment. Prophylactic anti-histamines and steroids did not reduce the risk of reaction. Whilst the mechanisms remain uncertain we can confirm that rapid desensitization is a safe and effective way of re-introducing an antibiotic to a patient with a non-immediate reaction. [Copyright &y& Elsevier]

This paper comprises part of the work of the Enhancing Teaching-Learning Environments in Undergraduate Courses project (Project web site http://www.ed.ac.uk/etl). The emphasis is on the content of a course unit, and in particular on the effect of the choice of learning aids deployed on students' attitudes to the course unit. [ABSTRACT FROM AUTHOR]

Abstract1. The Eastern Brownsnake, Pseudonaja textilis, is a large (to 2 m), slender-bodied, highly venomous elapid that causes most snakebite human fatalities in Australia. The response of recently captured snakes to human harassment was quantified. Using high-speed film, the type of neck display, time taken to strike, strike accuracy, strike speed and effectiveness of bite were recorded. 2. The snakes were surprisingly tolerant of harassment, especially at body temperatures similar to those that they exhibit in the field during the activity season. Smaller snakes spent more time trying to escape than did larger snakes. Most snakes gave warning prior to the strike, 58% by full (high) display and 19% by partial (low) display. Some 25% of strikes were bluff. 3. Body temperature (over the range 18–36 °C) had little effect on most of the variables measured, including: the frequency of display and bluff, the duration of the strike (mean 0·28 s), the strike distance (mean 0·34 m), the mean overall strike speed (1·1 m s-1, range 0·25–1·80), the mean fastest strike speed (during 1/25 s, = 1·7 m s-1, range 0·3–3·4), or the accuracy of the strike. 4. Instead, the type of prestrike display was related to strike speed and accuracy: strikes preceded by a full neck display were slower but more accurate (and more likely to involve venom transfer) than those preceded by minimal display. 5. Contrary to popular opinion, Eastern Brownsnakes are reluctant to deliver firm bites in response to human harassment even when continuously provoked. It is estimated that only 15% of the strikes recorded had the potential to cause significant envenomation. [ABSTRACT FROM AUTHOR]

Clinical information systems and electronic records are starting to appear in secondary care and herald new potentials for improving health provision and capturing high quality data. In 2006, we set up a program to develop electronic patient records (EPR) for chronic disease using Cystic Fibrosis (CF) as our initial model. Seven years on we are now exploring the real time clinical data to identify risks, trends and outcomes in chronic disease management. We are also working to establish new models of integration and to connect information between the client and all areas of health care. [ABSTRACT FROM AUTHOR]

Objectives Hypersensitivity reactions to beta-lactam antibiotics remain a major clinical problem in the management of patients with CF. Whilst reactions are more likely to occur in sicker patients receiving more frequent treatment this is not always the case and genetic predisposition may play a role. Methods Patients were recruited from the Leeds Adult CF Centre. High resolution sequence based typing was performed on HLA A, B, C, DRB1, DQA1, and DQB1. The data was compared to our electronic patient records. Results 263 patients took part in the study. 163 had a history of beta-lactam reactions and 100 were tolerant controls. 97 patients had a history of piperacillin hypersensitivity. No statistical differences in frequencies of single HLA alleles were seen between hypersensitive patients and controls. One haplotype (A*0201:B*4402:DRB1*0401) occurred at a higher frequency in patients with piperacillin reactions (OR 15.3; p = 0.0006). Conclusion The high frequency of beta-lactam reactions in patients with CF makes it unlikely that a single HLA allele could account for increased predisposition alone. This study shows interesting data supporting an increased genetic risk in certain individuals and more work is needed to refine this further. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Delayed-type β-lactam hypersensitivity develops in subset of patients. The cellular immunological processes that underlie the drug-specific response have been described; however, little is known about involvement of the humoral immune system. Thus, the aim of this study was to utilize piperacillin hypersensitivity as an exemplar to (i) develop cell culture methods for the detection of drug-specific B-cell responses, (ii) characterize drug-specific IgG subtypes and (iii) assess reactivity of IgG antibodies against proteins modified to different levels with piperacillin haptens. Methods IgG secretion and CD19+ CD27+ expression on B cells were measured using ELISPOT and flow cytometry, respectively. A piperacillin- BSA adduct was used as an antigen in ELISA antibody binding studies. Adducts generated using different ratios of drug to protein were used to determine the degree of conjugation required to detect IgG binding. Results B cells from hypersensitive patients, but not controls, were stimulated to secrete IgG and increase CD27 expression when cultured with soluble piperacillin. A piperacillin- BSA adduct with cyclized and hydrolysed forms of the hapten bound to eight lysine residues was used to detect hapten-specific IgG 1-4 subclasses in patient plasma. Hapten inhibition and the use of structurally unrelated hapten- BSA adducts confirmed antigen specificity. Antibody binding was detected with antigens generated at piperacillin/ BSA ratios of 10:1 and above, which corresponded to a minimum epitope density of 1 for antibody binding. Conclusion These data show that antigen-specific B lymphocytes and T lymphocytes are activated in piperacillin-hypersensitive patients. Further work is needed to define the role different IgG subtypes play in regulating the iatrogenic disease. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity reactions ( DHRs) are a matter of great concern, both for outpatient and in hospital care. The evaluation of these patients is complex, because in vivo tests have a suboptimal sensitivity and can be time-consuming, expensive and potentially risky, especially drug provocation tests. There are several currently available in vitro methods that can be classified into two main groups: those that help to characterize the active phase of the reaction and those that help to identify the culprit drug. The utility of these in vitro methods depends on the mechanisms involved, meaning that they cannot be used for the evaluation of all types of DHRs. Moreover, their effectiveness has not been defined by a consensus agreement between experts in the field. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology has organized a task force to provide data and recommendations regarding the available in vitro methods for DHR diagnosis. We have found that although there are many in vitro tests, few of them can be given a recommendation of grade B or above mainly because there is a lack of well-controlled studies, most information comes from small studies with few subjects and results are not always confirmed in later studies. Therefore, it is necessary to validate the currently available in vitro tests in a large series of well-characterized patients with DHR and to develop new tests for diagnosis. [ABSTRACT FROM AUTHOR]

Background For certain HLA allele-associated drug hypersensitivity reactions, the parent drug has been shown to associate directly with the risk allele. In other forms of hypersensitivity, HLA risk alleles have not been identified and T cells are activated in an allele unrestricted manner. Chemically reactive drug metabolites bind to multiple proteins; thus, it is assumed that the derived peptide antigens interact with a number of HLA molecules to activate T cells; however, HLA restriction of the drug metabolite-specific T-cell response has not been studied. Objective To utilize T cells from sulfamethoxazole ( SMX) hypersensitive patients with cystic fibrosis to examine the HLA molecules that interact with nitroso SMX ( SMX-NO)-derived antigens. Methods T-cell clones were generated from 4 hypersensitive patients. Drug-specific proliferative responses and cytokine secretion were measured. Anti-human class I and class II antibodies were used to analyse HLA restriction. Antigen-presenting cells expressing different HLA molecules were used to determine the alleles involved in the presentation of SMX-NO-derived antigens to T cells. Results A total of 976 clones were tested for SMX-NO reactivity. Thirty-nine CD4+ clones were activated with SMX-NO and found to proliferate and secrete cytokines. The SMX-NO-specific response was blocked with an antibody against HLA-DQ. SMX-NO-specific responses were detected with antigen-presenting cells expressing HLA-DQB1*05:01 (patient 1) and HLA-DQB1*02:01 (patient 2), but not other HLA-DQB1 alleles. Conclusion and Clinical Relevance HLA-DQ plays an important role in the activation of SMX-NO-specific CD4+ T cells. Detection of HLA-DQ allele-restricted responses suggests that T cells are activated by a limited repertoire of SMX-NO-modified peptides. [ABSTRACT FROM AUTHOR]

Objective Procalcitonin (PCT), a precursor of calcitonin is selectively raised in bacterial infections. The aim of this pilot study was to investigate the role of PCT as a surrogate marker of infection in adults with CF and to discriminate between infection and inflammation in patients with elevated C reactive protein (CRP). Methods Adults with CF receiving hospital intravenous antibiotics for a pulmonary exacerbation were recruited. PCT levels were prospectively measured in patients with elevated C reactive protein (CRP). Results To date 11 subjects, median (range) age, 32 (21–51) yrs have been investigated. CRP and Procalcitonin levels were 185 (69–283) mg/L and 0.3 (<0.01–49.8) ug/L respectively. In five cases, PCT levels were ≤0.2 ug/L despite significant elevation in CRP. In two cases PCT levels were ≤0.1 ug/L and a clinical diagnosis of viral illness or a Tazocin reaction were suspected. In both cases full resolution occurred after discontinuing antibiotics. The highest PCT levels occurred in a patient with a CRP of 381 mg/L and following severe Influenza A H3 (seasonal) infection. Conclusion PCT is a more specific marker of severe infection than conventional markers such as CRP. Preliminary data suggests that PCT may be useful in discriminating between severe pulmonary and endobronchial infection as well as noninfectious inflammation. This study is ongoing. [ABSTRACT FROM AUTHOR]

Objectives Metabolic alkalosis is a recognised complication of CF. The condition appears to occur during both clinical stability and during pulmonary exacerbations. The aim of this study was to explore the relationship between metabolic alkalosis, clinical status and blood biochemistry. Methods A retrospective review of electronic patient records (2007–2013) was undertaken for all patients attending the Leeds Adult CF Unit who had a blood gas analysed. Demographic data, diabetic status, pancreatic status, CF liver disease, sputum microbiology and blood electrolytes were extracted for the most recent blood gas for each individual. Results A total of 568 samples were analysed from 124 subjects. Median age was 30 years (range 17–69). pH was normally distributed but the curve was shifted to the right with a median pH of 7.44 (range 7.1–7.66). Full data was available for 120 subjects. Reduced FEV1% (p ≤ 0.0001), elevated MRC dyspnoea score (p ≤ 0.0001), low BMI (p = 0.02), chronic Pseudomonas status (p<0.05) and use of intravenous antibiotics (p ≤ 0.01) were associated with higher blood gas bicarbonate levels. Although there was no association between bicarbonate and potassium, magnesium or sodium plasma levels, there was an inverse correlation with plasma chloride (r = –0.557, p<0.0001). Conclusion Metabolic alkalosis is a common complication of CF and is associated with worse clinical status, antibiotic therapy and reduced plasma chloride. The aetiology remains unclear and cannot be explained by simple electrolyte depletion. [ABSTRACT FROM AUTHOR]

Anaphylaxis is a systemic allergic reaction, potentially life-threatening that can be due to nonoccupational or, less commonly, to occupational triggers. Occupational anaphylaxis (OcAn) could be defined as anaphylaxis arising out of triggers and conditions attributable to a particular work environment. Hymenoptera stings and natural rubber latex are the commonest triggers of OcAn. Other triggers include food, medications, insect/mammal/snake bites, and chemicals. The underlying mechanisms of anaphylactic reactions due to occupational exposure are usually IgE-mediated and less frequently non-IgE-mediated allergy or nonallergic. Some aspects of work-related allergen exposure, such as route and frequency of exposure, type of allergens, and cofactors may explain the variability of symptoms in contrast to the nonoccupational setting. When assessing OcAn, both confirmation of the diagnosis of anaphylactic reaction and identification of the trigger are required. Prevention of further episodes is important and is based on removal from further exposure. Workers with a history of OcAn should immediately be provided with a written emergency management plan and an adrenaline auto-injector and educated to its use. Immunotherapy is recommended only for OcAn due to Hymenoptera stings. [ABSTRACT FROM AUTHOR]

Background Electronic care records (ECRs) for cystic fibrosis (CF) provide a basis for accurate, reliable capture of clinical measures and interventions, and epidemiological trends, providing the basis for improved efficiency and patient safety. Methods A primary care system was modified for hospital use and clinical codes devised for all aspects of CF care. Performance and usability were assessed. Results Of a total of 620 patients 619 consented to their data being recorded in the system. Five hundred and twenty three new codes were created and embedded behind 60 new templates. Following introduction of ECR, completion of annual assessments increased from 43% to 92%, retrieval of drug costs rose significantly and time to correspondence with primary care fell from 34 days to < 2 days. Staff satisfaction was high. Conclusion The system is fully operational allowing the unit to function as a paperless service. Efficiencies of staffing activity, process management and cost retrievals are evident. Sharing of coding structures is important in future care. [ABSTRACT FROM AUTHOR]

Abstract: Background: Respiratory viruses have become increasingly recognised as important agents in pulmonary exacerbations in infants and children with CF. The aim of this study was to determine the prevalence of respiratory viruses during acute pulmonary exacerbations in adults and compare the severity of these exacerbations with non-viral associated exacerbations. Methods: This was a retrospective case control study. Viral throat swabs were taken from all patients presenting with an acute pulmonary exacerbation requiring intravenous antibiotic treatment over a 12month period. Results: There were 432 pulmonary exacerbations in 180 adults. A positive viral PCR in 42 exacerbations indicated a prevalence of 9.7%. The commonest virus isolated was rhinovirus (n =29, 69%) with influenza A/H1N1 in seven patients (16.7%). Exacerbations associated with a positive viral PCR had a greater fall in lung function at presentation with higher levels of inflammatory markers. They received more days of intravenous antibiotics, showed less response to treatment and had a shorter time to next pulmonary exacerbation compared to matched controls. Conclusion: Viral associated pulmonary exacerbations in adults with CF are associated with more severe pulmonary involvement and respond less well to standard treatment. [Copyright &y& Elsevier]

Drug hypersensitivity may deprive patients of drug therapy, and occasionally no effective alternative treatment is available. Successful desensitization has been well documented in delayed drug hypersensitivity reactions. In certain situations, such as sulfonamide hypersensitivity in HIV-positive patients or hypersensitivity to antibiotics in patients with cystic fibrosis, published success rates reach 80%, and this procedure appears helpful for the patient management. A state of clinical tolerance may be achieved by the administration of increasing doses of the previously offending drug. However, in most cases, a pre-existent sensitization has not been proven by positive skin tests. Successful re-administration may have occurred in nonsensitized patients. A better understanding of the underlying mechanisms of desensitization is needed. Currently, desensitization in delayed hypersensitivity reactions is restricted to mild, uncomplicated exanthems and fixed drug eruptions. The published success rates vary depending on clinical manifestations, drugs, and applied protocols. Slower protocols tend to be more effective than rush protocols; however, underreporting of unsuccessful procedures is very probable. The decision to desensitize a patient must always be made on an individual basis, balancing risks and benefits. This paper reviews the literature and presents the expert experience of the Drug Hypersensitivity Interest Group of the European Academy of Allergy and Clinical Immunology. [ABSTRACT FROM AUTHOR]

Abstract: There is a trend today to develop zirconia toughened alumina (ZTA) composites for orthopaedic applications. So far, there is limited data concerning their sensitivity to ageing, especially considering tests performed on implants produced on an industrial scale. Here, complementary tools were used to assess the ageing resistance of ZTA femoral heads. The results were compared to femoral heads processed under the same industrial process with monolithic 3Y-TZP. As expected, monolithic 3Y-TZP implants exhibited significant ageing. In contrast ZTA femoral head showed no sign of degradation even over a period equivalent to that of a human life. The potential impact of coupling effects between wear and ageing is assessed. Monolithic zirconia and ZTA femoral heads were thus first worn in a hip joint simulator, and then aged in autoclave. The kinetics of transformation of the worn monolithic zirconia implants is accelerated while that of worn ZTA femoral heads remains almost unchanged. [Copyright &y& Elsevier]