Journal of Cystic Fibrosis

Antimicrobial activity of fosfomycin and tobramycin in combination against cystic fibrosis pathogens under aerobic and anaerobic conditions

Gerard McCaughey, Matt McKevitt, J. Stuart Elborn, Michael M. Tunney — 2011-12-05

Abstract: Background: There is a need for new antibiotics or combination of antibiotics that possess activity against increasingly resistant cystic fibrosis (CF) respiratory pathogens such as Pseudomonas aeruginosa and MRSA.Methods: The antimicrobial activity of a novel 4:1 (w/w) fosfomycin:tobramycin (F:T) combination against CF respiratory pathogens under both aerobic and anaerobic conditions was determined by MIC, time-kill and biofilm studies, and compared with activity of fosfomycin and tobramycin, individually.Results: F:T and fosfomycin had excellent activity against P. aeruginosa and were more active than tobramycin against P. aeruginosa under anaerobic conditions with lower MIC50, MIC90 and geometric mean values. F:T (p<0.001) and fosfomycin (p<0.001) MICs for P. aeruginosa were significantly lower under anaerobic conditions with tobramycin MICs significantly higher (p<0.001). F:T and fosfomycin also had high activity against MRSA with both being more active than tobramycin. In time–kill studies, F:T was rapidly bactericidal against all 15 P. aeruginosa and 3/5 MRSA isolates tested. F:T also demonstrated bactericidal activity against P. aeruginosa grown in biofilm under both aerobic and anaerobic conditions.Conclusions: F:T has promising in vitro antimicrobial activity against MRSA and P. aeruginosa with greater activity under anaerobic conditions similar to those found in the CF lung.

Increasing resistance of the Liverpool Epidemic Strain (LES) of Pseudomonas aeruginosa (Psa) to antibiotics in cystic fibrosis (CF)—A cause for concern?

Abdul Ashish, Matthew Shaw, C. Winstanley, Martin J. Ledson, Martin J. Walshaw — 2011-12-07

Abstract: Background: Transmissible Pseudomonas aeruginosa (Psa) strains such as the Liverpool Epidemic Strain (LES) are now widespread throughout UK CF clinics: their susceptibility to antibiotics is therefore important. To study this, we compared antibiogram patterns of Psa strains in our CF clinic over 5years, looking at differences in resistance patterns between strains and changes to these over time.Methods: The antibiograms of sputum samples between 2004 and 2008 from patients attending our centre were included. We compared Psa isolate antibiotic resistance (to six anti-pseudomonal antibiotics) patterns for patients infected with LES with those infected with other Psa strains, both in the total population in 2004 (125 patients) and 2008 (166 patients) and also longitudinally from annual review samples 2004 to 2008 in matched and unmatched patient groups.Results: LES exhibited significantly more resistant isolates in 2004 (p<0.0001). There was an increase in antibiotic resistance in both LES and other Psa strains over time (p<0.001). Cox proportional hazards analysis of both unmatched (n=125) and matched (n=56) patients in 2004 revealed that LES infected patients were more likely to develop antibiotic resistant isolates over time (hazard ratio 8.1, p<0.001). Fewer LES isolates were classed as fully sensitive in both matched and unmatched groups at the end of study period (p<0.001).Conclusion: This study shows a worrying trend in antibiotic resistance in the Psa isolates amongst patients chronically infected with LES. This highlights the need to prevent cross infection through segregation and also the need to develop new strategies to treat these organisms.

Patient indicators of a pulmonary exacerbation: Preliminary reports from school aged children map onto those of adults

J. Abbott, A. Holt, A.M. Morton, A. Hart, G. Milne, S.P. Wolfe, S.P. Conway — 2011-12-15

Abstract: Background: Despite the importance of identifying and managing a pulmonary exacerbation, and its use as an outcome measure in interventions, there is no standardised definition in cystic fibrosis. In achieving standardised criteria it is important to identify patient-reported indicators.Methods: Interviews were undertaken with 35 school aged children. They reported symptoms experienced during a pulmonary exacerbation in two ways: the first symptoms they become aware of, and how they recognised when they were improving. Interviews were taped, transcribed verbatim and the data analysed thematically.Results: For many children, the onset of an exacerbation was characterised by ‘cold’ symptoms, tiredness, and changes in cough. For those with moderate or severe disease, sleep disruption, activity induced breathlessness, changes in mood, sputum volume and lack of appetite were common. When describing improvement children focused initially on activities they were now able to perform accompanied by improvements in tiredness and cough. Those with moderate or severe disease also reported improvements in sleep and mood, breathlessness, sputum volume and colour.Conclusions: Child-reported indicators of a pulmonary exacerbation tend to map onto those reported by adults. These results provide the rationale for the development of a single scale for school age children and adults that could be sensitive to progressive stages of CF disease.

Long-term non-invasive ventilation in cystic fibrosis — Experience over two decades

2011-12-19

Abstract: Background: Non-invasive ventilation (NIV) is accepted as a bridge to lung transplantation in cystic fibrosis (CF) but there is little evidence to support its use outside this setting.Methods: We reviewed the records of all patients with CF who received domiciliary NIV at our centre between 1991 and 2010.Results: Of 47 patients studied, 36% underwent lung transplantation, 28% died without transplantation and 30% remain alive on NIV. Median duration of NIV was 16months (range 2–90). Mean FEV1 fell by 212ml over the year before NIV but increased by 18ml in the following year (p<0.01). Individual response to NIV was associated with lower baseline and more rapid decline in FEV1. From 1991 to 2000, 70% underwent lung transplantation; from 2001 to 2010 only 27% were transplanted.Conclusions: NIV may slow or reverse the decline in lung function in advanced CF. NIV is increasingly used beyond a bridge to transplantation at our centre.

IL-17A as a regulator of neutrophil survival in nasal polyp disease of patients with and without cystic fibrosis

L. Derycke, N. Zhang, G. Holtappels, T. Dutré, C. Bachert — 2011-12-19

Abstract: Nasal polyps in adults are characterized by a chronic inflammation of the upper airways and by the preferential activation of Th2 cells. In contrast, IL-17 producing Th17 cells dominate the inflammation in nasal polyps of cystic fibrosis (CF) patients.Method: IL-17A, IL-5, IL-6, IL-8, IL-1β, ECP, MCP-1 and myeloperoxidase expression was determined in tissue homogenates of nasal polyps of non-CF and CF patients and controls. The cellular source of IL-17A was determined by immuno-histochemistry and FACS analysis. The functional role of IL-17A in the survival of neutrophils from CF and non-CF patients was tested.Results: A significant upregulation of IL-17A and myeloperoxidase could be observed in nasal polyps from CF-patients. The cellular sources of IL-17A in nasal polyps were mainly T-lymphocytes. IL-17A was able to modulate the survival of neutrophils in nasal polyps from non-CF patients; however the survival of neutrophils in CF patients was independent of IL-17A.Conclusion: The present study shows that IL-17A has an impact on neutrophil survival in adult nasal polyp disease, but not in nasal polyps from CF patients.

Small macrophages are present in early childhood respiratory disease

2011-12-21

Abstract: Background: Recently, an established “small macrophage” phenotype has been observed in the sputum of patients with CF and COPD. However, little is known about the prevalence of this phenotype in the airways of young children. Since respiratory inflammation begins early in CF, we hypothesised that these small macrophages would be increased in paediatric CF bronchoalveolar lavage (BAL).Methods: Macrophage populations in CF and disease control BAL were assessed by multicolour flow cytometry. BAL inflammatory indices were collected as part of the AREST-CF programme.Results: Small macrophages were present in CF (n=35, mean 36±12% of BAL macrophages) but not significantly different to the respiratory disease controls (n=7, mean 40±21%). Number of small macrophages correlated significantly with number of BAL neutrophils (r=0.44, p<0.01) but not infection or IL-8.Conclusions: In paediatric patients small macrophages are not unique to CF, but their establishment as the dominant phenotype in adults may be due to chronicity of inflammation and infection.

Effect of acute exacerbations on skeletal muscle strength and physical activity in cystic fibrosis

2012-01-06

Abstract: Background: Skeletal muscle weakness is an important complication of chronic respiratory disease. The effect of acute exacerbations on strength in patients with cystic fibrosis is not known.Methods: Quadriceps (QMVC) and respiratory muscle strength were measured in patients at the time of acute admission, at discharge and one month later. Patients wore an activity monitor during admission and at one month. Convalescent values were compared to the stable clinic population.Results: Data were available for 13 acute admissions and 25 stable CF outpatients. Strength and other parameters including daily step count did not differ significantly between the stable and one month post-admission groups. At admission, QMVC was 16.7 (8.3)% lower than at convalescence, whereas inspiratory muscle strength did not change significantly. Reduction in QMVC did not correlate with activity levels or with markers of systemic inflammation.Conclusion: Further research is needed to identify the mechanisms responsible for the reduction in QMVC.

Feasibility of using pedometers to measure daily step counts in cystic fibrosis and an assessment of its responsiveness to changes in health state

2012-01-06

Abstract: Background: Evaluation of physical activity is integral to the assessment of daily physical function and a potential objective outcome measure for clinical trials. We evaluated the feasibility of using pedometers to measure physical activity in adolescents and adults with cystic fibrosis (CF) and assessed the responsiveness of its measurement to changes in health state.Methods: Participants were recruited through two CF clinics in Seattle, WA. Subjects were instructed to use their pedometer for at least one ill and two well periods (each lasting 7days). Step rate was calculated as steps per hour of use. Daily symptoms were also recorded using the CF Respiratory Symptom Diary (CFRSD). Generalized estimating equation linear regression was used to compare mean step rate between health states and by self-reported symptom category.Results: We enrolled 30 CF patients with a mean (±SD) age of 22 (±7) years and a mean forced expiratory volume in 1s (FEV1) of 57% (±25%) predicted. The mean period step rate increased from 397 (95% CI 324–497) steps/hour when ill to 534 (95% CI 413–654) steps/hour when well (p=0.015). Pedometer-recorded step rate also correlated with self-reported physical activity items on the CFRSD.Conclusion: Step rate measured with a pedometer correlates significantly with changes in health status and self-reported activity, and could be used as an outcome measure in CF.

Determining presence of lung disease in young children with cystic fibrosis: Lung clearance index, oxygen saturation and cough frequency

E.M. Bakker, J.C. van der Meijden, E.M. Nieuwhof, W.C.J. Hop, H.A.W.M. Tiddens — 2012-01-24

Abstract: Background: Accurate assessment of pulmonary status in young children with cystic fibrosis (CF) requires sensitive and objective monitoring techniques.Objectives: This study aimed to evaluate the feasibility of lung clearance index (LCI) calculated from multiple breath washout (MBW), home nocturnal pulse oximetry and home nocturnal cough recording in young children with CF, and determine whether these tests can distinguish CF patients from healthy controls.Methods: We performed a prospective cross-sectional study in 20 CF patients and 30 healthy children aged 0–4years. MBW was performed in awake and unsedated children at the outpatient clinic using a commercially available device. Measurements of nocturnal oxygen saturation and nocturnal cough were done at home using a pulse oximeter and an audiometer.Results: There was a significant difference in mean LCI between healthy children and CF patients (LCI 7.1 vs. 9.3, p<0.001). Nocturnal oxygen saturation was normal in both groups and did not significantly differ between the groups. Similarly, cough showed no differences between both groups. Cough varied widely between children and between nights. Success rates for saturation and cough measurements were 90% and were similar for CF patients and healthy children. Success rate for LCI was 75% for CF patients and 50% for healthy children.Conclusions: Measurements of LCI, nocturnal oxygen saturation and cough were feasible in young children; however LCI was the only variable that showed a significant difference between children with CF and healthy children.

A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference

Anissa Leonard, Patrick Lebecque, Jasper Dingemanse, Teresinha Leal — 2012-01-27

Abstract: Background: Preclinical data suggest that miglustat could restore the function of the cystic fibrosis transmembrane conductance regulator gene in cystic fibrosis cells.Methods: Single-center, randomized, double-blind, placebo-controlled, crossover Phase II study in 11 patients (mean±SD age, 26.3±7.7years) homozygous for the F508del mutation received oral miglustat 200mgt.i.d. or placebo for two 8-day cycles separated by a 14-day washout period. The primary endpoint was the change in total chloride secretion (TCS) assessed by nasal potential difference.Results: No statistically significant changes in TCS, sweat chloride values or FEV1 were detected. Pharmacokinetic and safety were similar to those observed in patients with other diseases exposed to miglustat.Conclusions: There was no evidence of a treatment effect on any nasal potential difference variable. Further studies with miglustat need to adequately address criteria for assessment of nasal potential difference.

Ivacaftor potentiation of multiple CFTR channels with gating mutations

2012-02-01

Abstract: Background: The investigational CFTR potentiator ivacaftor (VX-770) increased CFTR channel activity and improved lung function in subjects with CF who have the G551D CFTR gating mutation. The aim of this in vitro study was to determine whether ivacaftor potentiates mutant CFTR with gating defects caused by other CFTR gating mutations.Methods: The effects of ivacaftor on CFTR channel open probability and chloride transport were tested in electrophysiological studies using Fischer rat thyroid (FRT) cells expressing different CFTR gating mutations.Results: Ivacaftor potentiated multiple mutant CFTR forms with defects in CFTR channel gating. These included the G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P and G1349D CFTR gating mutations.Conclusion: These in vitro data suggest that ivacaftor has a similar effect on all CFTR forms with gating defects and support investigation of the potential clinical benefit of ivacaftor in CF patients who have CFTR gating mutations beyond G551D.

Voriconazole pharmacokinetics and photosensitivity in children with cystic fibrosis

Sophia L. Markantonis, Anna Katelari, Eleni Pappa, Stavros Doudounakis — 2012-01-27

Abstract: Background: A high incidence of adverse skin reactions following long-term oral administration of voriconazole in children with cystic fibrosis and allergic bronchopulmonary aspergillosis (ABPA). The aim was to study the pharmacokinetics of voriconazole in these patients and to determine a possible association between drug levels and adverse effects.Methods: Multiple venous blood samples were collected for HPLC determination of voriconazole concentrations and routine blood tests. Adverse events were recorded.Results: No significant correlation was found between incidence of photosensitivity and voriconazole serum levels in 6 of 8 children with ABPA. 80% of patients had trough voriconazole concentrations<1000ng/mL and were highly variable.Conclusions: Long-term voriconazole therapy and greater sun exposure in Greece appear to play a major role in the occurrence of photosensitivity. Steady-state plasma drug concentrations were found to be highly variable and below the recommended therapeutic range in most patients, without any apparent negative influence on outcome.

Six minute walk test Z score: Correlations with cystic fibrosis severity markers

2011-12-22

Abstract: Background: The six-minute-walk-test (6MWT) has been increasingly used in cystic fibrosis (CF) patients. However, few studies in children have correlated 6MWT with current parameters used to evaluate CF severity. Moreover, no study transformed the values of distance walked from meters into Z scores to avoid bias like age and gender, which are sources of 6MWT variability.Methods: A cross-sectional descriptive study was performed to analyze the correlations (Spearman) among forced expiratory volume in one second (FEV1), body mass index (BMI), chest radiography (CXR), chest tomography (CT), and 6MWT Z score (Z-6MWT). Clinically stable CF patients, aged 6–21years, were included.Results: 34 patients, 14F/20M, mean age 12.1±4.0years were studied. The mean Z-6MWT was −1.1±1.106. The following correlations versus Z-6MWT were found: FEV1 (r=0.59, r2=0.32, p=0.0002), BMI Z score (r=0.42, r2=0.17, p=0.013), CXR (r=0.34, r2=0.15, p=0.0472) and CT (r=−0.45, r2=0.23, p=0.0073).Conclusions: In conclusion there was a significant, but poor, correlation between the six minute walk test Z score and the cystic fibrosis severity markers currently in use.

Impact of IVS8-(TG)m(T)n on IRT and sweat chloride levels in newborns identified by California CF newborn screening

2012-01-03

Abstract: We examined the relation between the number of (TG) repeats at the (IVS8)-(TG)m(T)5 locus of the CFTR gene with neonatal serum immunoreactive trypsinogen (IRT) and sweat chloride (SC) concentrations in hypertrypsinogenemic infants with genotype ΔF508-9T/5T identified by California cystic fibrosis newborn screening. SC and IRT distributions increased with increasing (TG) repeats.

Acknowledgment of referees

2012-02-13