The diagnosis and management of respiratory tract fungal infection in cystic fibrosis: A UK survey of current practice.

Aspergillus fumigatus is commonly found in the airways of patients with cystic fibrosis (CF), and allergic bronchopulmonary aspergillosis (ABPA) is the most recognized associated clinical condition. However, accurate diagnosis remains challenging, and there is a paucity of clinical trials to guide clinical management of fungal disease. The aim of this survey was to assess the variability in current practice across the UK in diagnosis and management of fungal lung disease in CF patients. A 21 question anonymous online survey was sent to 94 paediatric and adult CF consultants in the UK. The response rate was 60.6% (32 adult physicians, 25 pediatricians) with 55 full and 2 partially completed surveys. For a first diagnosis of ABPA 20 (35.1%) treat with prednisolone alone, 38 (66.7%) use prednisolone with itraconazole and 2 (3.5%) choose voriconazole. Only 5 (8.8%) treat with prednisolone alone for a 1st relapse, 33 (58%) used prednisolone with itraconazole. To reduce treatment, 21 (36.8%) decrease steroids to zero over time and maintain azole therapy, 18 (31.6%) stop the azole and steroid after a fixed time, and 5 (8.8%) stop the azole after a fixed time and maintain a small steroid dose. Thirty-eight (66.7%) respondents believe Aspergillus colonization of the airway can cause clinical deterioration, and 37 (66.1%) would treat this. Scedosporium apiospermum infection has been diagnosed and treated by 35 (61.4%) of respondents. Results of this survey highlight the variance in clinical practice and the limited evidence available to guide management of fungal infection in CF.

Microscopic polyangiitis secondary to Mycobacterium abscessus in a patient with bronchiectasis: a case report.

BACKGROUND: Non-Tuberculous Mycobacterial-pulmonary disease (NTM-PD) is increasing in incidence and prevalence. Mycobacterium abscessus (M.abscessus) is a rapid growing multi-resistant NTM associated with severe NTM-PD requiring prolonged antibiotic therapy. Complications of therapy are common but reports on direct complications of active NTM-PD are rare. Vasculitis has been described as a rare complication of NTM-PD, most often in individuals with inherited immune defects. This case is the first to describe an ANCA positive vasculitide (Microscopic Polyangiitis) secondary to M.abscessus pulmonary disease. CASE PRESENTATION: A 70 year old female with bronchiectasis underwent a clinical decline associated with the growth of M.abscessus and was diagnosed with NTM-PD. Before treatment could be initiated she developed small joint arthralgia and a glove and stocking axonal loss sensorimotor neuropathy. Positive Perinuclear Anti-Neutrophil Cytoplasmic Antibodies (P-ANCA) and Myeloperoxidase-ANCA (MPO-ANCA) titres led to a diagnosis of microscopic polyangiitis. Further investigation revealed reduced interferon-gamma production but no other significant immune dysfunction. Dual treatment with immunosuppressive therapy (Corticosteroids/Cyclophosphamide) for vasculitis and antimicrobial therapy for M.abscessus NTM-PD was initiated. Clinical stability was difficult to achieve with reductions in immunosuppression triggering vasculitic flares. One flare led to retinal vein occlusion with impending visual loss requiring escalation in immunosuppression to Rituximab infusions. An increase in immunosuppression led to a deterioration in NTM-PD necessitating alterations to antibiotic regimes. Adverse effects including alopecia and Achilles tendonitis have further limited antibiotic choices resulting in a strategy of pulsed intra-venous therapy to stabilise NTM-PD. CONCLUSIONS: This is the first reported case of an ANCA positive vasculitis secondary to M.abscessus pulmonary disease. This rare but important complication had a significant impact on the patient adding to the complexity of an already significant disease and treatment burden. The potential role of reduced interferon-gamma production in this case highlights the importance of investigating immune function in those with mycobacterial infection and the intricate relationship between mycobacterial infection and immune dysfunction. Immune dysfunction caused by genetic defects or immunosuppressive therapy is a known risk factor for NTM-PD. Balancing immunosuppressive therapy with prolonged antimicrobial treatment is challenging and likely to become more common as the number of individuals being treated with biologics and immunosuppressive agents increases.

Does ivacaftor interfere with the antimicrobial activity of commonly used antibiotics against Pseudomonas aeruginosa?-Results of an in vitro study.

WHAT IS KNOWN AND OBJECTIVE: Ivacaftor is a novel potentiator of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein, which corrects the gating defect and increases ion-function of activated cell-surface CFTR. Bacteria also regulate their physiology through ion channels. However, little is known about the potential effects of ivacaftor on bacterial ion channels, which, in turn, may have a potential effect on transport across the bacterial cell membrane. Therefore, any change in the ability to transport molecules across cell membranes in bacteria could have an important impact on bacterial transport physiology. One area where this could be particularly important is in the movement of antibiotics, both into and out of the bacterial cell. An in vitro study was therefore performed to examine the influence of ivacaftor at therapeutic concentration on antibiotic susceptibility of 11 commonly used anti-pseudomonal antibiotics against a population of clinical Pseudomonas aeruginosa [PA], from CF and non-CF sources. METHOD: Pseudomonas aeruginosa (n = 80; including 70 ivacaftor-naïve clinical PA from sputa from adult CF patients and 10 control PA from non-CF clinical blood culture sources) were examined. Antibiotic susceptibility was determined by standard disc diffusion assay using CLSI criteria and measuring zone size (mm), against four classes of anti-pseudomonal antibiotics, including beta-lactams (temocillin, ceftazidime, piperacillin/tazobactam, imipenem, meropenem and aztreonam), aminoglycosides (gentamicin, tobramycin, amikacin), fluoroquinolone (ciprofloxacin) and polymyxin (colistin), in the absence and presence of ivacaftor (5 µmol/L), as previously determined. In addition, all CF and non-CF PA were examined phenotypically in vitro, as previously described, for changes linked to bacterial virulence, including (i) growth density (ii) pigmentation, (iii) presence of adhesins and (iv) change to mucoidy, in the presence/absence of ivacaftor at therapeutic concentration. RESULTS AND DISCUSSION: Antibiotic susceptibility did not decrease significantly with any of the antibiotics examined with CF PA isolates or with non-CF PA control organisms. There was a statistically significant increase in zone size (CF PA and amikacin, gentamicin, temocillin and ciprofloxacin; Non-CF PA and amikacin, gentamicin and aztreonam). However, at a population level, this did not translate into a shift in CLSI category to a more susceptible phenotype. None of the PA isolates examined were susceptible to ivacaftor alone, and additionally, no changes were noted with the four phenotypic parameters examined in the presence of ivacaftor. WHAT IS NEW AND CONCLUSION: This study showed that antibiotic susceptibility of commonly used anti-pseudomonal antibiotics was not negatively affected by ivacaftor, in a population of ivacaftor-naive P. aeruginosa.

Pseudomonas aeruginosa in cystic fibrosis patients with c.1652G>A (G551D)-CFTR treated with ivacaftor-Changes in microbiological parameters.

WHAT IS KNOWN AND OBJECTIVE: The CFTR potentiator, ivacaftor (IVA), has been widely used in the treatment of cystic fibrosis (CF) patients with the G551D mutation. To date, there has been limited information on the microbiological status of patients on this therapy and no data on the effect (if any) on the in vivo antibiotic susceptibility of Pseudomonas aeruginosa isolated from patients on therapy. Although IVA intervention is not designed per se as anti-infective, the effect (if any) of this molecule to CF patients' microbiological status merits careful monitoring. Therefore, it was the aim of this observational study to examine the effect in patients, both before and after commencement of IVA therapy, on several commonly reported microbiological markers in CF patients, including (i) bacterial density, (ii) frequency (rate) of isolation of bacterial pathogens, particularly P. aeruginosa, and (iii) antimicrobial susceptibility of these isolates to commonly prescribed oral and iv antibiotics. In addition, we wished to examine the requirements for these antibiotics in CF patients, before and after commencement of IVA therapy. METHODS: Archived data from 15 adult cystic fibrosis patients with the c.1652G>A (G551D) mutation were followed from two years pre-IVA therapy to two years after commencement of IVA therapy. The microbiological parameters examined included (i) oral antibiotic courses taken, (ii) intravenous (iv) antibiotic courses taken, (iii) rate of isolation of non-mucoid Pseudomonas aeruginosa (NM-PA) and mucoid P. aeruginosa (M-PA), (iv) density of NM-PA and M-PA and (v) antimicrobial susceptibility of NM-PA and M-PA to 11 antibiotics [aminoglycosides, beta-lactams, polymyxin and fluoroquinolone]. RESULTS AND DISCUSSION: Following commencement of IVA therapy, patients required less iv antibiotic courses but no change in number of oral antibiotics courses. There was significant reduction in both the rate of isolation and density of M-PA (P = .02; P = .006, respectively). In contrast, there was no significant reduction in both the rate of isolation and density of NM-PA (P = .90; P = .07, respectively). Antimicrobial susceptibility in NM-PA and M-PA was not significantly reduced within any of the antibiotics classes or individual antibiotics examined. Increased susceptibility was noted in the beta-lactam class for NM-PA and M-PA, in particular with ceftazidime. WHAT IS NEW AND CONCLUSION: Overall, (i) the requirement for less iv antibiotic therapy, (ii) a reduction in the rate and density of M-PA and (iii) no reduction in antibiotic susceptibility indicate that microbiological parameters with patients on IVA therapy were not detrimentally affected.

Pseudomonas aeruginosa displays an altered phenotype in vitro when grown in the presence of mannitol.

D-mannitol has been approved in dry powder formulation as an effective antimucolytic agent in patients with cystic fibrosis. What is not known is the effect of adding a metabolisable sugar on the biology of chronic bacterial pathogens in the CF lung. Therefore, a series of simple in vitro experiments were performed to examine the effect of adding D-mannitol on the phenotype of the CF respiratory pathogens Pseudomonas aeruginosa and Burkholderia cenocepacia. Clinical isolates (n = 86) consisting of P. aeruginosa (n = 51), B. cenocepacia (n = 26), P. putida (n = 4), Stenotrophomonas maltophila (n = 3) and Pseudomonas spp. (n = 2) were examined by supplementing basal nutrient agar with varying concentrations of D-mannitol (0-20% [w/v]) and subsequently examining for any change in microbial phenotype. The effect of supplementation with mannitol was four-fold, namely i) To increase the proliferation and increase in cell density of all CF organisms examined, with an optimal concentration of 2-4% (w/v) D-mannitol. No such increase in cell proliferation was observed when mannitol was substituted with sodium chloride. ii) Enhanced pigment production was observed in 2/51 (3.9%) of the P. aeruginosa isolates examined, in one of the P. putida isolates, and in 3/26 (11.5%) of the B. cenocepacia isolates examined. iii). When examined at 4.0% (w/v) supplementation with mannitol, 11/51 (21.6%) P. aeruginosa isolates and 3/26 (11.5%) B. cenocepacia isolates were seen to exhibit the altered adhesion phenotype. iv). With respect to the altered mucoid phenotype, 5/51 (9.8%) P. aeruginosa produced this phenotype when grown at 4% mannitol. Mucoid production was greatest at 4%, was poor at 10% and absent at 20% (w/v) mannitol. The altered mucoid phenotype was not observed in the B. cenocepacia isolates or any of the other clinical taxa examined. Due consideration therefore needs to be given, where there is altered physiology within the small airways, leading to a potentially altered biological state of the colonising microorganisms in novel inhaled pharmaceutical interventions in CF, particularly those, which are not designated as antimicrobial agents.

ECFS standards of care on CFTR-related disorders: Identification and care of the disorders.

This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). This paper covers the individual disorders, including the established conditions - congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis - and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided. Gaps in our knowledge, particularly of the emerging conditions, and future areas of research, including the role of CFTR modulators, are highlighted.

Building global development strategies for cf therapeutics during a transitional cftr modulator era.

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

Neutrophils in cystic fibrosis.

Lung injury in cystic fibrosis is caused by recurrent airway infection and inflammation. Neutrophils are important in combating these infections but are also the predominate cells involved in the inflammatory process. This review of neutrophils in cystic fibrosis describes the cellular mechanisms involved in their migration into the airways and their role in bacterial phagocytosis. We discuss the inflammatory process and its resolution and ultimately how neutrophil function can be modulated.

In vitro antimicrobial activity of ceftolozane/tazobactam against Pseudomonas aeruginosa and other non-fermenting Gram-negative bacteria in adults with cystic fibrosis.

OBJECTIVES: Pulmonary exacerbations in patients with cystic fibrosis (CF) caused by chronic Gram-negative bacterial infections are associated with reduced survival. These pathogens are usually treated with repeated courses of systemic antimicrobial agents. However, there is associated emergence of multidrug-resistant (MDR) pathogens. Ceftolozane/tazobactam (C/T) is a novel cephalosporin/ß-lactamase inhibitor combination that has been demonstrated to have good activity against MDR Pseudomonas aeruginosa. METHODS: In this study, C/T was compared with other commonly used intravenous antimicrobial agents against 193 non-fermenting Gram-negative bacteria isolated from CF sputum specimens, including P. aeruginosa, Achromobacter xylosoxidans, Stenotrophomonas maltophilia and Burkholderia cenocepacia. Minimum inhibitory concentrations (MICs) to C/T were determined by standard Etest assay and were interpreted according to current European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. RESULTS: C/T had good in vitro antimicrobial activity against CF clinical isolates of P. aeruginosa in comparison with other antimicrobial agents, with the exception of colistin. C/T also had activity against S. maltophilia but was not active against B. cenocepacia or A. xylosoxidans. CONCLUSION: C/T showed excellent in vitro activity against P. aeruginosa CF clinical isolates. This antimicrobial agent is a potential therapeutic option when presented with challenging MDR P. aeruginosa and S. maltophilia exacerbations. Further clinical experience and trials in CF are required to determine the place of C/T in clinical practice.

Glucocorticoids as an adjuvant treatment to intravenous antibiotics for cystic fibrosis pulmonary exacerbations: a UK Survey.

Oral glucocorticoids are widely used to treat exacerbations of asthma and COPD. A role for their use in treating exacerbations in Cystic Fibrosis (CF) is not proven. We describe the current practice, amongst UK adult CF physicians, of oral glucocorticoid use as an adjuvant to intravenous (IV) antibiotic treatment during CF pulmonary exacerbation (P EX). The survey also examined whether physicians thought a randomised controlled trial (RCT) was necessary and their willingness to participate patients in such a trial. Eighty one percent of physicians replied. All of them used corticosteroids with P EX. Most physicians supported the need for a RCT and would be willing to enroll consenting patients in the trial. This survey highlighted the need for a RCT which would examine the role of adjuvant corticosteroids to IV antibiotics in CF P EX.

MRSA eradication in a health care worker with cystic fibrosis; re-emergence or re-infection?

Methicillin-resistant Staphylocosis aureus (MRSA) is an emerging infection in patients with cystic fibrosis (CF). MRSA may be a management dilemma for healthcare workers (HCWs) with CF. Eradication of MRSA with long-term rifampicin and fusidic acid can be achieved in patients with CF. We describe a case of recurrent MRSA infection in a HCW with CF. Molecular typing of the MRSA isolates supported re-infection rather than re-emergence of an earlier MRSA infection. Infection control advice for HCWs with CF who acquire MRSA remains controversial.

Microbial ecology of the cystic fibrosis lung: does microflora type influence microbial loading?

This study aims to examine the association between the numbers of culturable microbial species forming the microflora of the lung in patients with cystic fibrosis (CF) and microbial loading (i.e., type[s] versus numbers). Additionally, it examines qualitative combinations of the microflora present in a large adult CF centre (n=138) in order to ascertain ecological relationships between the taxa present. The culturable microflora of sputum from 34 adults patients with CF are enumerated using a spread plate technique on non-selective agar, and the microflora identified phenotypically employing the API 20NE scheme. Microbiological examination of the 34 adult patients demonstrated that their sputum contained between one and three taxa, with a mean cell density of 8.25 +/- 0.85 log colony-forming units (cfu)/g sputum and a range of 5.91-9.74 log cfu/g sputum. Most colonising patterns demonstrated only Gram-negative infection (22/34), followed by a mixed Gram-positive/Gram-negative infection pattern (10/34). Only 2/34 patients had a single Gram-positive infection. Most patients (53%) were colonised by only one organism, with 38% of patients colonised by two organisms, and the remainder (4%) colonised with three organisms. There was no statistical difference (P>0.05) between microbial cell density and the number of taxa present (i.e., the greater number of taxa present in sputum did not produce a higher cell density). However, there was a significantly higher cell density (log 0.59 cfu/g sputum) noted for those patients who had only Gram-negative infection, compared to those who had a mixed Gram-negative/Gram-positive infection pattern (P=0.02). Relatively little is known about the ecological interactions that exist between the microflora in the CF lung. Further work is required to explore these interactions in order to aid understanding of the succession and dominance of Gram-negatives in chronic chest infections. Ultimately, a greater understanding of such interactions may allow the opportunity to manipulate the ecology of the lung to control otherwise problematic pathogens

Eradication of Pseudomonas aeruginosa in adults with cystic fibrosis.

BACKGROUND: Eradication of new infection of Pseudomonas aeruginosa is an important intervention in managing cystic fibrosis (CF). Previous trials, studying predominantly under 18-year-olds, indicate that antibiotic eradication therapy (AET) has success rates of 62.8-93.0%. In this retrospective cohort study, we report the outcomes of AET in an adult population. METHODS: Adults with a confirmed diagnosis of CF and a first isolation of P aeruginosa were studied between 1999 and 2012. Choice of therapy, time to eradication and reinfection, and lung function (forced expiratory volume in 1 s (FEV1)) were determined. RESULTS: 20 patients (median age 27 years) isolated P aeruginosa during the study period. 10 patients were treated with oral ciprofloxacin (median duration 6 weeks) and nebulised colomycin (median duration 3 months). 7 patients were treated with intravenous antipseudomonal antibiotics (median duration 14 days). 2 patients received other combinations of oral and inhaled antipseudomonal therapy and one patient received no therapy. AET was successful in 15 cases who received antipseudomonal therapy (79%). The median time to eradication was 1 month. The median time to reinfection with P aeruginosa was 43 months. There was no significant change in FEV1 after 12 months. CONCLUSIONS: Aggressive AET of new infection of P aeruginosa in adults is successful in the majority of patients and has similar efficacy to the reported efficacy in paediatric populations.

Thoracic ultrasound for pleural effusion: delays and cost associated with departmental scanning.

Pleural effusion is a common clinical condition on medical wards and the majority of cases undergo pleural aspiration or chest drain insertion as a diagnostic or therapeutic procedure. The use of a thoracic ultrasound scan (USS) improves diagnostic yield for pleural fluid aspiration and reduces complications and USS is increasingly recommended prior to all pleural aspirations or drains and 'real time' scanning which, as well as potentially reducing delays, enhances the safety of the procedure. In many U.K hospitals a thoracic USS is still routinely performed in the radiology department. We reviewed radiology records and case notes from hospital in-patients to assess potential delays and associated costs with departmental thoracic USS and to identify cases where physician-led portable USS would potentially have improved the patient's journey. We demonstrated delays resulting in significant financial costs to the hospital of an estimated pound17, 880 per annum. However, the cost to the patient is also significant, both in terms of patient experience (many of whom will have an underlying diagnosis of metastatic carcinoma and with a limited life expectancy) but also patient safety. Respiratory physicians are increasingly recognising the importance of portable thoracic USS to guide pleural procedures and there has been increasing use of physician-led portable thoracic USS. Hospitals should be encouraged to fund both portable thoracic USS equipment but it is also crucial that training in this area is properly supported.