A network meta-analysis of the efficacy of inhaled antibiotics for chronic Pseudomonas infections in cystic fibrosis

BackgroundVarious inhaled antibiotics are currently used for treating chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients, however their relative efficacies are unclear. We compared the efficacy of the inhaled antibiotics tobramycin (TIP, TIS-T, TIS-B), colistimethate sodium (colistin) and aztreonam lysine for inhalation (AZLI) based on data from randomised controlled trials.MethodsIn the base case, efficacies of antibiotics were compared using a network meta-analysis of seven trials including change from baseline in forced expiratory volume in 1 second (FEV₁) % predicted, P. aeruginosa sputum density and acute exacerbations.ResultsThe tobramycin preparations, AZLI and colistin, showed comparable improvements in efficacy in terms of FEV1% predicted at 4 weeks; the difference in % change from baseline (95%CrI) for TIP was compared to TIS-T (- 0.55, - 3.5;2.4), TIS-B (- 0.64, - 7.1;5.7), AZLI (3.64, - 1.0;8.3) and colistin (5.77, - 1.2;12.8).ConclusionWe conclude that all studied antibiotics have comparable efficacies for the treatment of chronic P. aeruginosa lung infection in CF.     

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

BackgroundThere 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.MethodsThe 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.ResultsF: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.ConclusionsF: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.     

Validation of the Treatment Satisfaction Questionnaire for Medication in patients with cystic fibrosis

BackgroundOur objective was to confirm the measurement properties of the Treatment Satisfaction Questionnaire with Medication (TQSM) in patients with cystic fibrosis (CF) receiving inhaled antibiotics.MethodsThe TSQM was included in the EAGER study, a clinical trial comparing a nebulized and a dry powder device for inhaled tobramycin in a CF population with chronic Pseudomonas aeruginosa (Pa) lung infection, aged 6 years and above (N = 553). Reliability and validity of the questionnaire were investigated using Cronbach's α and multitrait–multimethod approach.ResultsThe TSQM demonstrated very good reliability and construct validity: all Cronbach's α were above 0.86 and all items met the convergent and discriminant validity criteria. In multivariate regressions, higher patient satisfaction and lower perceived impact of side-effects were associated with better treatment compliance.ConclusionsThe TSQM showed very good measurement properties that strongly support its use to assess satisfaction of patients with CF taking inhaled antibiotics.     

Effectiveness of inhaled tobramycin in eradicating Pseudomonas aeruginosa in children with cystic fibrosis

BackgroundInhaled tobramycin therapy has been shown to be efficacious in clinical trials for the eradication of initial Pseudomonas aeruginosa infection in children with cystic fibrosis (CF). However, the effectiveness of different regimens in eradicating P. aeruginosa and preventing the development of chronic infection in actual clinical settings has yet to be determined.MethodsThis was an observational study of children (< 18 years of age) with CF with incident P. aeruginosa infection from 2005–2012 based on data collected from the Toronto CF Database and medical charts. Patients who received inhaled tobramycin (80 mg/2 ml twice daily for 365 days) were compared to those who received tobramycin inhalation solution (TIS) (300 mg/5 ml twice daily for 28 days) with respect to eradication and development of chronic infection. We also examined the risk factors for recurrence of infection.ResultsDuring the study period, 65 patients were identified with incident P. aeruginosa, of which 7 (11%) failed eradication therapy. Eradication failure was similar between the two treatment groups. A total of 4 patients (6%) developed chronic P. aeruginosa infection in the 12 months following the end of therapy with no differences between treatment groups. Female gender, older age, pancreatic insufficiency, lower lung function and worse nutritional status were identified as risk factors for recurrence of P. aeruginosa infection.ConclusionsBoth regimens of inhaled tobramycin have similar effectiveness in eradicating P. aeruginosa and preventing chronic P. aeruginosa infection in CF patients in clinical practice. Further work is needed, however, to identify patient characteristics and bacterial factors that play a role in eradication failure, in order to develop more effective antimicrobial rescue treatment strategies.     

A retrospective analysis of biofilm antibiotic susceptibility testing: A better predictor of clinical response in cystic fibrosis exacerbations

BackgroundBacteria grow as biofilms within CF airways. However, antibiotic susceptibility testing is routinely performed on planktonically-growing bacteria. This study assessed whether CF patients infected with multiresistant organisms had improved clinical outcomes if given antibiotics that inhibited their biofilm-grown bacteria.Methods110 patients with pulmonary exacerbations were treated with intravenous antibiotics based on susceptibility testing of planktonically-growing bacteria. A retrospective analysis was done using bacterial isolates grown from their sputum at exacerbation. Each isolate was grown as a biofilm and combination antibiotic susceptibility testing was performed. Clinical outcomes in patients treated with biofilm-susceptible antibiotics were compared to those that were not.Results66 of 110 patients (60%) were treated with antibiotic combinations that inhibited all of their planktonically-grown bacterial isolates, however, when the same isolates were grown as biofilms, only 24 patients (22%) had all of their biofilm-grown isolates remaining susceptible to the antibiotics (P = < 0.001 ). When patients with at least one biofilm-grown susceptible isolate (n = 61) were compared to those with none (n = 49), there was a significant decrease in sputum bacterial density (P = 0.02) and length of stay (P = 0.04) and a non-significant decrease in treatment failure. Survival analyses of time to next exacerbation showed non-significant trends favoring patients treated with biofilm-effective antibiotics.ConclusionsMost patients with CF exacerbations do not receive antibiotics that inhibit all biofilm-grown bacteria from their sputum at exacerbation. Patients treated with biofilm-effective therapy seemed to have improved clinical outcomes.     

Inhaled versus nebulised tobramycin: A real world comparison in adult cystic fibrosis (CF)

BackgroundThere are no published data on real-life clinical experience comparing inhaled antibiotic therapy via new rapid delivery systems with nebulised antibiotic therapy in CF. This real world study compares safety, effectiveness and tolerability using tobramycin inhaled powder (TIP) versus tobramycin inhaled solution (TIS).MethodsAdult patients with CF commencing TIP (n = 78) completed a questionnaire assessing safety, efficacy, tolerability, patient-satisfaction and self-reported adherence to TIS at baseline and during 12 months of TIP therapy. FEV₁% predicted and exacerbation rate were recorded at each visit.ResultsThere was a significant improvement in adherence scores, with a significant decrease in the number of intravenous antibiotic courses received during 12 months of TIP compared with the preceding 12 months using TIS. 94% of patients who had previously used TIS preferred TIP therapy over TIS.ConclusionsInhaled powder tobramycin in CF is associated with improved adherence, tolerability and decreased exacerbation rates compared to nebulised treatment in real-life practice.     

Epidemiology and resistance of Achromobacter xylosoxidans from cystic fibrosis patients in Dijon,Burgundy: First French data

BackgroundAchromobacter xylosoxidans is an emerging pathogen in cystic fibrosis (CF) patients recognised as causal agent of inflammation. The prevalence of infection or colonisation is variable among CF centres. We report here the first epidemiological data about A. xylosoxidans in a French CF centre: Dijon, Burgundy.MethodsAll isolates recovered from the patients affiliated with our centre in 2010 since their first visit were included. Antimicrobial susceptibility was determined by disk diffusion method and E-test. Molecular epidemiology was performed by Pulsed Field Gel Electrophoresis (PFGE) and compared with repetitive sequence-based PCR (rep-PCR, DiversiLab®). We also sequenced the constitutive bla-_oxa-114 gene.ResultsOut of 120 patients, 21 (17.5%) had at least one positive culture with A. xylosoxidans since they started to receive routine care in our CF centre (447 isolates). Median age at first positive culture was 16 years (range 3–34 years). Most patients were colonised by their own strain, cross-contamination was very rare. We observed two cases of intra-family spread. DiversiLab® is a useful tool as efficient as PFGE to compare isolates recovered simultaneously from different patients when an outbreak is suspected. However, PFGE remains the reference method for long-term survey of chronically colonised patients. We detected new OXA-114 variants and the new oxacillinase OXA-243 (88% amino acid identity with OXA-114). Acquired resistance to ciprofloxacin, ceftazidime and carbapenems was frequent. In 2010, 7 patients harboured strains resistant to ceftazidime, 6 patients strains with decreased susceptibility to carbapenems (especially meropenem) and 12 patients strains resistant to ciprofloxacin.ConclusionsIn our centre, the high prevalence of colonisation is not due to cross-contamination. Our main concern is the high rate of antimicrobial resistance.     

Inhaled amiloride and tobramycin solutions fail to eradicate Burkholderia dolosa in patients with cystic fibrosis

BackgroundBurkholderia dolosa can result in chronic airway infection and rapid decline in lung function in patients with cystic fibrosis (CF). Amiloride has antibacterial properties that may be synergistic with aminoglycosides against other species belonging to the Burkholderia cepacia complex (Bcc). We attempted to eradicate B. dolosa using a combination of nebulized tobramycin and nebulized amiloride in infected CF patients.MethodsA 6-month, open-label trial of continuous inhaled amiloride, delivered via nebulization four times daily, and continuous inhaled tobramycin (TIS or TOBI®) nebulized twice daily, was offered to all CF patients at our institution who are chronically infected with B. dolosa.ResultsTwenty two of 27 patients with B. dolosa were eligible and twelve elected to participate. Eradication of B. dolosa was not noted in any study subject. While patients tolerated treatment with no adverse effects, there was also no apparent impact on other secondary outcome measures.ConclusionsConcurrent, continuous inhalation of amiloride and tobramycin for 6 months was not effective for the eradication of chronic B. dolosa airway infection in CF patients.     

Safety of inhaled (Tobi®) and intravenous tobramycin in young children with cystic fibrosis

BackgroundUse of inhaled tobramycin therapy for treatment of Pseudomonas aeruginosa infections in young children with cystic fibrosis (CF) is increasing. Safety data for pre-school children are sparse.MethodsThe aim of this study was to assess the safety of tobramycin solution for inhalation (TOBI®-TSI) administered twice daily for 2 months/course concurrently to intravenous (IV) tobramycin during P. aeruginosa eradication therapy in children (0–5 years). Audiological assessment and estimation of glomerular filtration rate (GFR) was measured prior to any exposure and end of the study.ResultsData were available from 142 patients who were either never exposed to aminoglycosides (n = 39), exposed to IV aminoglycosides only (n = 36) or exposed to IV + TSI (n = 67). Median exposure to TSI was 113 days [59, 119]. Comparison of effects on audiometry results and GFR, showed no detectable difference between the groups.ConclusionsUse of TSI and IV tobramycin in pre-school children with CF was not associated with detectable renal toxicity or ototoxicity.     

Impact of azithromycin on the clinical and antimicrobial effectiveness of tobramycin in the treatment of cystic fibrosis

Background

Concomitant use of oral azithromycin and inhaled tobramycin occurs in approximately half of US cystic fibrosis (CF) patients. Recent data suggest that this combination may be antagonistic.

Efficacy and tolerability of a new nasal spray formulation containing hyaluronate and tobramycin in cystic fibrosis patients with bacterial rhinosinusitis

BackgroundChronic rhinosinusitis is common in cystic fibrosis (CF), as CFTR defects equally affect the airway and sinonasal mucosa. However, therapeutic strategies for CF-associated chronic rhinosinusitis lag behind current approaches for pulmonary disease.ObjectiveTo assess the tolerability and efficacy of a nasal spray formulation containing 0.2% sodium hyaluronate and 3% tobramycin compared to a control formulation containing 0.2% sodium hyaluronate alone in the treatment of bacterial rhinosinusitis in patients with CF.MethodsIn a double-blind controlled study, 27 patients with an established diagnosis of CF and a documented nasal infection with Pseudomonas aeruginosa and/or Staphylococcus aureus [22 males (81%), median age of 15 years (range 5–26 yrs)], were randomized to receive the nasal spray formulation containing hyaluronate and tobramycin (N = 14) or hyaluronate alone (N = 13) for 14 days. Efficacy and local tolerability of the treatments were assessed by ear, nose and throat (ENT) examination and related symptoms.ResultsThe formulation containing hyaluronate and tobramycin was more effective than hyaluronate alone in improving the status of the nasal mucosa, in reducing the mucopurulent secretion at the level of the osteomeatal complex and in improving ENT symptoms (hyposmia/anosmia and headache/facial pain). The treatment was well tolerated without relevant side effects.ConclusionsThe present study suggests that the combination therapy with hyaluronate plus tobramycin was more effective than hyaluronate alone in the treatment of bacterial rhinosinusitis in CF. Trial registration number: EudraCT 2007-003628-39.     

Timing of inhaled tobramycin affects assessment of intravenous tobramycin pharmacokinetic monitoring

BackgroundAerosolized tobramycin inhalation solution (TIS) may be absorbed and result in measurable serum concentrations. We assessed the significance of TIS dosing in the latter portion of the IV dosing interval on the calculation of pharmacokinetic (PK) parameters and dosing.MethodsTwenty adult CF patients admitted to the hospital for treatment of a pulmonary exacerbation were enrolled. PK parameters of tobramycin were calculated before and after introduction of TIS, which was given 5–9 h after the IV dose.ResultsNine patients had a clinically significant change in tobramycin trough concentration. Fourteen patients had a reduced calculated elimination rate constant after TIS administration, which may be misinterpreted as a decreased clearance of IV tobramycin.ConclusionTrough tobramycin concentrations were significantly influenced in some CF patients (45%), suggesting that timing of the inhaled dose should be considered when interpreting PK measures of IV tobramycin dosing.     

Prevalence and risk factors for recovery of filamentous fungi in individuals with cystic fibrosis

BackgroundFilamentous fungi are frequently recovered from respiratory cultures of individuals with CF.MethodsA CF cohort database was utilized to determine filamentous fungal prevalence and risk factors.ResultsThe prevalence of filamentous fungal isolation increased from 2.0% in 1997 to 28.7% in 2007. The odds of isolating filamentous fungi during a quarter was greater in CF adults [p < 0.001], during chronic oral antibiotic use [p = 0.002] and increased with each 10% drop in FEV₁ percent predicted [p = 0.005], while inhaled corticosteroids surprisingly decreased the likelihood [p = 0.012]. The direction of these effects persisted after excluding individuals with ABPA. A sub-analysis determined older age [p = 0.019] and use of inhaled antibiotics [p = 0.011] were independent risk factors for onset of fungal colonization.ConclusionsThis study suggests that isolation of filamentous fungi in CF at JHH has increased and risk factors include older age, decreased lung function, and chronic oral antibiotics.     

Differences in prevalence and treatment of Pseudomonas aeruginosa in cystic fibrosis centres in Denmark,Norway and Sweden

BackgroundChronic Pseudomonas aeruginosa (PA) infection causes increased morbidity and mortality in cystic fibrosis (CF). This study aimed to answer the following questions: Does the prevalence of chronic infection with PA differ between the CF centres in Scandinavia? Which differences exist concerning segregation and treatment of PA?Methods989 patients (86%) from all eight CF-centres in Scandinavia were included. Demographic and clinical data, including PA colonisation status based on cultures and serology, were recorded at inclusion. The patients were followed prospectively for 1 year, recording number of days with anti-PA antibiotic treatment.ResultsIn all pancreatic insufficient (PI) patients (n = 890) the prevalence of chronic PA infection at each centre ranged from 25.8% to 48.9%, but were not significantly different. In PI patients < 19 years the prevalence was 14.5% in Copenhagen compared to 30.9% in the Swedish centres pooled (p = 0.001). In intermittently colonised PI patients < 19 years the median number of days per year on anti-PA antibiotics was almost 6 times higher in Copenhagen (mean 86 (110), median 61 days) compared to the Swedish centres pooled (mean 27 (52), median 11 days) (p = 0.037). The pulmonary function was similar.ConclusionsIt is possible to maintain a very low prevalence of chronic PA infection in CF patients < 19 years. We speculate that this was most likely due to a very intensive treatment of intermittently colonised patients with inhaled anti-PA antibiotics over prolonged periods of time in some centres. Since lung function was similar in centres with less intensive use of inhaled antibiotics, studies comparing different treatment modalities and other parts of CF care are needed to define the best clinical practice, including how to use antibiotics in the most rational way.     

Early aggressive eradication therapy for intermittent Pseudomonas aeruginosa airway colonization in cystic fibrosis patients: 15 years experience

BackgroundSince 1989, CF-patients intermittently colonized with Pseudomonas aeruginosa have been treated with inhaled colistin and oral ciprofloxacin in the Copenhagen CF-centre. The study evaluates 15 years results of this treatment.MethodsAll isolates of P. aeruginosa from CF-patients intermittently colonized with P. aeruginosa from 1989 to 2003 were identified All anti-P. aeruginosa treatments were evaluated for antibiotics used, treatment duration, pseudomonas-free interval and development of chronic infection. All P. aeruginosa isolates were assessed for resistance and for non-mucoid or mucoid phenotype.Results146 CF-patients were included in the study (1106 patient-years). 99 patients had first ever isolate during the study period. Median observation time 7 years (0.1–14.9). 12 patients developed chronic infection. A Kaplan Meyer plot showed protection from chronic infection in up to 80% of patients for up to 15 years. 613 colistin/ciprofloxacin treatments were given. There was no difference in pseudomonas-free interval comparing 3 weeks (5 months) and 3 months (10.4 months) of colistin and ciprofloxacin, but a significant difference compared to no treatment (1.9 months). Patients developing chronic infection had significantly shorter pseudomonas-free interval after treatment of first ever isolate compared to patients remaining intermittently colonized (p < 0.003). Treatment failure (P. aeruginosa-positive culture immediately after ended treatment of first ever isolate) was a strong risk factor for development of chronic infection after 3–4 years, OR 5.8. 1093 pseudomonas-isolates were evaluated (86.6% non-mucoid). No colistin-resistance was found. Ciprofloxacin-resistance was found in 4% of isolates.ConclusionTreatment of intermittent P. aeruginosa colonization in CF-patients using colistin and ciprofloxacin can protect up to 80% of patients from development of chronic infection for up to 15 years. A positive culture immediately after treatment of first ever isolate is a strong risk factor for development of chronic infection. We found no colistin-resistance and minimal ciprofloxacin-resistance.     

Mycobacterium avium and Mycobacterium abscessus complex target distinct cystic fibrosis patient subpopulations

BackgroundClinical observations suggest that Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) may affect cystic fibrosis (CF) patients with different characteristics and risk factors, but this has never been demonstrated within a single prospective cohort.MethodsWe studied 50 MABSC-positive and 23 MAC-positive patients from a French prevalence study of non‐tuberculous mycobacteria (NTM) in CF. Risk factors specifically associated with MABSC and MAC were analyzed by nested case–control studies, with two NTM-negative controls matched by age, sex and center for each case.ResultsMAC-positive patients were significantly older than MABSC-positive patients (mean [SD] age, 23.1 [10.2] vs 17.4 [8.3] years, p = 0.013), and were also older at CF diagnosis (mean [SD] age, 12.9 [16.1] vs 3.1 [7.7] years, p = 0.015); they tended to be less frequent of the ΔF508/ΔF508 genotype (33.3 vs 61.1%, p = 0.17) and to use pancreatic extracts less frequently (82.4 vs 97.6%, p = 0.07). Risk factors identified by multivariate analysis were: i) in the MAC case–control study, an older age at CF diagnosis (p = 0.004); ii) in the MABSC case–control study, at least one course of intravenous antibiotics (p = 0.01) and more frequent isolation of Aspergillus (p = 0.03).ConclusionsMAC affects adult patients with a mild form of CF, whereas MABSC affects younger patients with more severe CF and more frequent intravenous antimicrobial treatment.     

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

BackgroundTransmissible 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 5 years, looking at differences in resistance patterns between strains and changes to these over time.MethodsThe 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.ResultsLES 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).ConclusionThis 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.     

Pharmacokinetics and safety of tobramycin administered by the PARI eFlow® rapid nebulizer in cystic fibrosis

BackgroundNebulization times have been identified as an issue in patient compliance with tobramycin solution for inhalation (TSI) therapy in cystic fibrosis (CF).MethodsIn this randomized, open-label, multicentre, two-period, crossover study, patients (n = 25) with CF and chronic pulmonary pseudomonal infection received TSI for 15 days via eFlow rapid or LC PLUS nebulizer. Nebulization times and sputum/serum tobramycin concentrations were determined, and safety evaluated.ResultsNebulization times were significantly shorter for eFlow rapid versus LC PLUS on Day 1 (least squares mean estimate of the difference − 10.5 min, 95% confidence intervals [CI] − 12.6, − 8.3, p < 0.0001) and Day 15 (difference − 7.7 min, 95% CI − 9.0, − 6.5, p < 0.0001). Broadly comparable sputum/systemic exposure to tobramycin was observed and the incidence of adverse events was similar for both nebulizers.ConclusionUse of the eFlow rapid nebulizer reduced TSI nebulization time. The systemic exposure to tobramycin appeared to be broadly similar in this exploratory study.