Efficacy and safety of azithromycin maintenance therapy in primary ciliary dyskinesia (BESTCILIA): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Use of maintenance antibiotic therapy with the macrolide azithromycin is increasing in a number of chronic respiratory disorders including primary ciliary dyskinesia (PCD). However, evidence for its efficacy in PCD is lacking. We aimed to determine the efficacy and safety of azithromycin maintenance therapy for 6 months in patients with PCD. METHODS: The Better Experimental Screening and Treatment for Primary Ciliary Dyskinesia (BESTCILIA) trial was a multicentre, double-blind, parallel group, randomised, placebo-controlled phase 3 trial done at 6 European PCD clinics (tertiary paediatric care centres and university hospitals in Denmark, Germany, Netherlands, Switzerland, and UK). Patients with a confirmed diagnosis of PCD, aged 7-50 years old, and predicted FEV1 greater than 40% were recruited. Participants were randomly assigned (1:1), stratified by age and study site, via a web-based randomisation system to azithromycin 250 mg or 500 mg as tablets according to bodyweight (

Catheter-related bloodstream infections in patients with intestinal failure receiving home parenteral support: risks related to a catheter-salvage strategy.

Background: In intestinal failure (IF) patients receiving home parenteral support (HPS), catheter-related bloodstream infections (CRBSIs) frequently result in replacement of their tunneled central venous catheters (CVCs), which may lead to future loss of central venous access. Objective: This observational study investigated the consequences of a catheter-salvage strategy related to CRBSIs. Design: All CRBSIs from 2002 to 2016 in the Copenhagen IF and microbiological databases were retrospectively analyzed. Catheter salvage was defined by successful antimicrobial therapy with a retained CVC at discharge. Re-occurrences of CRBSIs with the same microbial species and identical antibiogram were defined as a relapse (<30 d) or as a recurrent (30-100 d) infection. Cox regression analyses incorporated a frailty factor to account for recurrent events and overrepresentation by some patients. Cumulative incidence curves are presented with a competing risk model. Results: There were 2006 tunneled CVCs inserted in 715 adult HPS patients covering 2014.3 CVC years, with a CRBSI incidence rate of 1.83/1000 (n = 1350) and a mortality rate of 0.007/1000 CVC days (n = 5). The mean ± SD salvage rate was 55.3% ± 5.5%, varying according to infection type [monoinfections (62.9% ± 4.4%) and polyinfections (58.6% ± 17.3%)] and causative microorganism [coagulase-negative Staphylococci (CoNS) (68.1% ± 9.4%), Staphylococcus aureus (42.6% ± 17.5%), and Enterobacteriaceae (54.3% ± 16.7%)]. The overall risk of CRBSI relapse was 7.5%, and the risk of CRBSI recurrence was 7.3%. The HR for a subsequent CRBSI was 14% lower in a replaced than in a retained CVC (95% CI: 0.74, 0.99). The HR for a new CRBSI after catheter salvage was 36% higher after polyinfections than after monoinfections (95% CI: 1.03, 1.79). Enterobacteriaceae entailed an increased risk of CRBSI recurrence compared with CoNS (2.26; 95% CI; 1.08, 4.75) and S. aureus (4.45; 95% CI: 1.28, 15.5). Conclusions: High catheter-salvage rates related to CRBSIs were achievable and safe in HPS patients within a broad range of microorganisms but contributed to an increased risk of CRBSI relapse or recurrence.

Catheter-Related Bloodstream Infections in Adults Receiving Home Parenteral Nutrition: Substantial Differences in Incidence Comparing a Strict Microbiological to a Clinically Based Diagnosis.

BACKGROUND: A common complication in patients receiving home parenteral nutrition (HPN) is catheter-related bloodstream infections (CRBSIs). The CRBSI incidence has been advocated as an outcome parameter assessing the quality of care. This study aimed to illustrate how the use of different CRBSI definitions affects the reported incidence. MATERIALS AND METHODS: In an observational study based on the Copenhagen intestinal failure database, all clinically reported CRBSIs from 2002-2013 were compared with data from the affiliated microbiological database according to recommended CRBSI criteria. RESULTS: Clinically, 1034 CRBSIs were observed in 548 adults receiving HPN for 1410 catheter-years. Thus, the clinically assessed CRBSI incidence was 1.95/1000 catheter-days. However, based on the microbiological evaluation, only 47% of our episodes fulfilled the Centers for Disease Control and Prevention (CDC) and European Society for Clinical Nutrition (ESPEN) CRBSI criteria. Employing a catheter-salvaging strategy, 40% of the CRBSI diagnoses were supported by the paired blood culture positivity criteria and only 6% by a positive catheter tip. In 53%, CRBSIs were categorized as a clinical or "probable CRBSI" diagnosis. In 20% of all episodes, missing information/blood cultures hampered a CDC/ESPEN CRBSI diagnosis. Thereby, according to CDC/ESPEN CRBSI definitions, the incidence was 0.92/1000 days or 46% lower than clinically assessed. CONCLUSION: This study illustrates the practical and methodological challenges and great variability in reporting of the CRBSI incidence. Nonetheless, it is recommended as a marker of the quality of care. Consensus regarding CRBSI definitions is a prerequisite for a meaningful comparison of this important outcome parameter between HPN centers.

Taurolidine-citrate-heparin lock reduces catheter-related bloodstream infections in intestinal failure patients dependent on home parenteral support: a randomized, placebo-controlled trial.

Background: In patients with intestinal failure who are receiving home parenteral support (HPS), catheter-related bloodstream infections (CRBSIs) inflict health impairment and high costs.Objective: This study investigates the efficacy and safety of the antimicrobial catheter lock solution, taurolidine-citrate-heparin, compared with heparin 100 IE/mL on CRBSI occurrence.Design: Forty-one high-risk patients receiving HPS followed in a tertiary HPS unit were randomly assigned in a double-blinded, placebo-controlled trial. External, stratified randomization was performed according to age, sex, and prior CRBSI incidence. The prior CRBSI incidence in the study population was 2.4 episodes/1000 central venous catheter (CVC) days [95% Poisson confidence limits (CLs): 2.12, 2.71 episodes/1000 CVC days]. The maximum treatment period was 2 y or until occurrence of a CRBSI or right-censoring because of CVC removal. The exact permutation tests were used to calculate P values for the log-rank tests.Results: Twenty patients received the taurolidine-citrate-heparin lock and 21 received the heparin lock, with 9622 and 6956 treatment days, respectively. In the taurolidine-citrate-heparin arm, no CRBSIs occurred, whereas 7 CRBSIs occurred in the heparin arm, with an incidence of 1.0/1000 CVC days (95% Poisson CLs: 0.4, 2.07/1000 CVC days; P = 0.005). The CVC removal rates were 0.52/1000 CVC days (95% Poisson CLs: 0.17, 1.21/1000 CVC days) and 1.72/1000 CVC days (95% Poisson CLs: 0.89, 3.0/1000 CVC days) in the taurolidine-citrate-heparin and heparin arm, respectively, tending to prolong CVC survival in the taurolidine arm (P = 0.06). Costs per treatment year were lower in the taurolidine arm (€2348) than in the heparin arm (€6744) owing to fewer admission days related to treating CVC-related complications (P = 0.02).Conclusions: In patients with intestinal failure who are life dependent on HPS, the taurolidine-citrate-heparin catheter lock demonstrates a clinically substantial and cost-beneficial reduction of CRBSI occurrence in a high-risk population compared with heparin. This trial was registered at clinicaltrials.gov as NCT01948245.

Multiple hospital outbreaks of vanA Enterococcus faecium in Denmark, 2012-13, investigated by WGS, MLST and PFGE.

OBJECTIVES: In Denmark, the incidence of vancomycin-resistant Enterococcus faecium (VREfm) has increased since 2012. The aim of this study was to investigate the epidemiology and clonal relatedness of VREfm isolates in Danish hospitals in 2012-13 using WGS. The second aim was to evaluate if WGS-based typing could replace PFGE for typing of VREfm. METHODS: A population-based study was conducted including all VREfm isolates submitted for national surveillance from January 2012 to April 2013. All isolates were investigated by WGS, MLST and PFGE. RESULTS: One-hundred and thirty-two isolates were included. The majority of the isolates were from clinical samples (77%). Gastroenterology/abdominal surgery (29%) and ICUs (29%) were the predominant departments with VREfm. Genomics revealed a polyclonal structure of the VREfm outbreak. Seven subgroups of 3-44 genetically closely related isolates (separated by <17 SNPs) were identified using WGS. Direct or indirect transmission of VREfm between patients and intra- and inter-regional spreading clones was observed. We identified 10 STs. PFGE identified four major clusters (13-43 isolates) and seven minor clusters (two to three isolates). The results from the typing methods were highly concordant. However, WGS-based typing had the highest discriminatory power. CONCLUSIONS: This study emphasizes the importance of infection control measures to limit transmission of VREfm between patients. However, the diversity of the VREfm isolates points to the fact that other important factors may also affect the VREfm increase in Denmark. Finally, WGS is suitable for typing of VREfm and has replaced PFGE for typing of VREfm in Denmark.