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.

Ultrasound and magnetic resonance imaging assessment of joint disease in symptomatic patients with cystic fibrosis arthropathy.

OBJECTIVES: Cystic fibrosis arthropathy (CFA) is a term commonly used for joint pain with and without swelling seen in some patients with CF. Early studies into CFA focused on the presence of rheumatoid factor and immunological changes on synovial biopsy, with parallels drawn between respiratory and joint activity. Identification of anti-cyclic citrullinated peptide antibodies (anti-CCP) as a marker of rheumatoid arthritis (RA), along with increased access to sensitive imaging techniques including ultrasound (US) and magnetic resonance imaging (MRI), offer great potential to investigate and more accurately understand the type(s) of inflammatory arthritis that may underlie CFA. The aim of this study was to phenotype an active CFA cohort using serology and imaging, as a basis for further work in this understudied area. METHODS: This was a prospective observational cohort study of symptomatic CFA patients presenting with joint pain. Participants underwent serological testing, clinical and US joint and entheseal assessment, as well as MRI of the most symptomatic joint/joint area. RESULTS: Ten symptomatic patients were studied with 9/10 having positive clinical findings. Inflammatory changes on US were seen in 8/10 cases. Five patients had positive findings on MRI (3 of whom had received IV gadolinium contrast). This included patients with significant erosive changes. One patient was anti-CCP positive suggestive of RA, and two were anti-nuclear antibody positive. CONCLUSION: Imaging, and to a lesser extent serology, identified inflammatory joint pathology in a proportion of cases, providing important data to explore in a large CFA cohort examining the clinical and imaging phenotype of this group.

HLA-DQ allele-restricted activation of nitroso sulfamethoxazole-specific CD4-positive T lymphocytes from patients with cystic fibrosis.

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.

Research in progress-electronic patient records: a new era.

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.

The development and deployment of integrated electronic care records in a regional adult and paediatric cystic fibrosis unit.

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 34days to <2days. 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.

The role of respiratory viruses in adult patients with cystic fibrosis receiving intravenous antibiotics for a pulmonary exacerbation.

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 12 month 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.

Desensitization in delayed drug hypersensitivity reactions -- an EAACI position paper of the Drug Allergy Interest Group.

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.

Rapid desensitization for non-immediate reactions in patients with cystic fibrosis.

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 48 h 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.

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.

Treatment of male urethral strictures: is repeated dilation or internal urethrotomy useful?

PURPOSE: We evaluate the efficacy of repeated dilation or urethrotomy as treatment of male urethral strictures. MATERIALS AND METHODS: Between January 1991 and January 1994, 210 men with proved urethral strictures were prospectively randomized to undergo filiform dilation (106) or internal urethrotomy (104). Followup was scheduled at 3, 6, 9, 12, 24, 36 and 48 months. Dilation or internal urethrotomy was repeated at the first and second stricture recurrence. The Kaplan-Meier method was used to estimate survivor function for the treatment methods (survival time being the time to first stricture recurrence) and the log rank test was used to compare the efficacy of different treatments. RESULTS: Followup (mean 24 months, range 2 to 63) was available in 163 patients (78%). After a single dilation or urethrotomy not followed by re-stricturing at 3 months, the estimated stricture-free rate was 55 to 60% at 24 months and 50 to 60% at 48 months. After a second dilation or urethrotomy for stricture recurrence at 3 months the stricture-free rate was 30 to 50% at 24 months and 0 to 40% at 48 months. After a third dilation or urethrotomy for stricture recurrence at 3 and 6 months the stricture-free rate at 24 months was 0 (p <0.0001). CONCLUSIONS: Dilation and internal urethrotomy are useful in a select group (approximately 70% of all patients) who are stricture-free at 3 months, and of whom 50 to 60% will remain stricture-free up to 48 months. A second dilation or urethrotomy for early stricture recurrence (at 3 months) is of limited value in the short term (24 months) but of no value in the long term (48 months), whereas a third repeated dilation or urethrotomy is of no value.

Probing the structure of influenza B hemagglutinin using site-directed mutagenesis.

The crystal structure of the hemagglutinin (HA) of influenza virus A/Aichi/68 (H3N2) from the X-31 reassortant virus was reported in 1981, but as yet there are no X-ray diffraction structures for hemagglutinins of other types or even subtypes of influenza virus. We have used site-directed mutagenesis to probe the structure of the hemagglutinin of influenza B/Hong Kong/8/73. We investigated a region in the globular head domain that is helical in the influenza A HA structure, targeting sidechains that in the H3 HA point toward solvent (Thr196) or into the receptor-binding pocket (Gln197). None of the mutations affected hemagglutination activity, but mutations T196P or Q1971 eliminated binding of a monoclonal antibody. The data suggest that this region of the influenza B HA forms a surface structure different from the alpha-helix of the influenza A HA structure and that it accounts for much of the antigenic activity of influenza B HA.

Identification of critical contact residues in the NC41 epitope of a subtype N9 influenza virus neuraminidase.

We have examined amino acids on influenza virus neuraminidase (NA) subtype N9 (A/tern/Australia/G70c/75) which are in contact with monoclonal antibody NC41 to analyze individual interactions important for antibody recognition. The crystal structure of NA complexed with NC41 Fab1 shows antibody contacts at 19 amino acid residues on the NA surface which are localized on five polypeptide loops surrounding the enzyme active site. Fifteen mutant NA genes were constructed to encode a protein which contained a single amino acid substitution and these were tested for effects of the replacement on NC41 binding. Our data revealed that NAs with changes at 368, 400, and 434 completely lost NC41 recognition. NAs with side chains replaced at residues 346 and 373 exhibited binding reduced to less than 50% of wild-type binding. Changes in seven other contacting residues, including substituted side chains which differed considerably from wild-type NA in size and charge, had no significant effect on NC41 binding. These results indicate that only a few of the many residues which make up an epitope are crucial for interaction and provide the critical contacts required for antibody recognition. This implies that antibody escape mutants are selected only if they contain changes at these crucial sites, or changes which introduce bulky side chains that sterically prevent antibody attachment.

Laparoscopy for the non-palpable testis--look before you cut!

Before definitive surgery laparoscopies were performed to define the position of 24 non-palpable testes in 21 patients. The anatomical site of the testes was confirmed by surgery in all cases. Laparoscopy is helpful in planning the definitive procedure in these cases.