J. Willekens

How long should we maintain long-term azithromycin treatment in cystic fibrosis patients?

We have read with interest the trial by Saiman et al., investigating the efficacy of azithromycin treatment in 146 Pseudomonas aeruginosa uninfected cystic fibrosis (CF) patients. Treatment resulted in a significant reduction in pulmonary exacerbations and a significant increase in weight gain after 12 months. However, the authors give no information about long-term treatment beyond 12 months. Up till now, azithromycin has been usedmainly as add-on treatment for chronicP. aeruginosa colonized CF patients. Nevertheless, the number of studies examining efficacy of azithromycin treatment in CF is limited, and the recommended dosage and duration of azithromycin treatment remains uncertain. A few randomized, placebo-controlled studies have shown a positive effect on pulmonary function, nutritional status and/or number of pulmonary exacerbations in both pediatric and adult CF patients. The longest duration of these studies is 12months. The only studywith a longer follow-up, an open retrospective study by TramperStranders et al. during 3 years, demonstrated a positive effect on FEV1% predicted in the first year after start of azithromycin, with a subsequent decline at the same rate as before therapy. Furthermore, placebo-controlled studies in P. aeruginosa colonized patients are limited. Only one trial studied the effect of azithromycin in a group of 185P. aeruginosa infected CF patients and found an improvement in FEV1 and a decreased number of pulmonary exacerbations in the azithromycin group after 6 months. Maintenance treatment with azithromycin was introduced in our center in 2004, as add-on therapy for chronically colonized P. aeruginosa CF patients who had experienced 2 or more pulmonary exacerbations in the past 6 months. Dosing schedule is 250mg three times a week in patients< 40 kg and 500mg three times a week in patients> 40kg. Most patients still continued this treatment, and this prompted us to question and reconsider its prolongation. We reviewed the medical files of all patients with chronic P. aeruginosa colonization (defined as having three or more positive cultures during at least 6 months follow-up), treated with azithromycin, age> 4 years and able to perform a reliable spirometry, and with a follow-up in our center of at least 3 years. Pulmonary function parameters (FEV1, FVC, and FEF25–75% predicted), body mass index (BMI) Z scores, and number of pulmonary exacerbations were analyzed at different time intervals: the year before azithromycin initiation, and the first, second and third year after azithromycin initiation. Pulmonary exacerbation was defined as increased cough, sputum, and/or dyspnea, requiring treatment with oral or intravenous antibiotics. Data were analyzed using SPSS 20.0 (SPSS, Inc., IBM, Chicago, IL). Pulmonary function values, BMI Z scores and number of pulmonary exacerbations were compared using student t tests. Statistical tests were two-sided and statistical significance was accepted at P< 0.05. A total of 50 patients were identified as having chronic P. aeruginosa colonization. Thirty one patients were started on azithromycin. Seven discontinued treatment prematurely after a median duration of 0.75 years (range 0.1–5.8), mainly due to gastro-intestinal adverse events. Three patients were excluded due to age< 4 years (one patient) or insufficient time of follow-up (two patients). Median age of patients was 29.6 years (range 13–47). Longest treatment duration was 7 years (median; range 4.5–8.6). Table 1 shows clinical characteristics of the patients. At the end of the first treatment year, no significant differences in pulmonary function parameters or BMI Z scores were found compared to the year before treatment start. However, the number of orally treated pulmonary exacerbations per patient decreased during the first treatment year (Fig. 1, P1⁄4 0.009), whereas no effect was seen on the more severe exacerbations, needing intravenous treatment (P1⁄4 0.13). The reduction of peroral antibiotic courses was not sustained in the second and third treatment year. In conclusion, in this single-center study, azithromycin treatment resulted in a reduction of orally treated

Increase in ventilated air spaces after eradication of chronic methicillin-resistant Staphylococcus aureus infection in cystic fibrosis patients

Abstract Effective microbiogical eradication of methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) can be obtained, but its effect is not always clear-cut in terms of spirometric indices. The aim of this observational prospective cohort study was to study the potential effect of eradication of chronic MRSA infection on lung function including ventilation distribution. Six CF patients, chronically colonized with MRSA (median age: 21 years (range 14–46); median FEV1: 76 (95%CI 58–98)%pred) were successfully eradicated using oral rifampicin and fusidic acid in combination with topical decolonization measures. Lung function and multiple breath washout test were performed at the start and at the end of the eradication protocol and after an average follow-up period of 7·5±1·5(SD) months. One patient cultured MRSA again 4 months after successful eradication. All patients reported reduced sputum production and viscosity. By the end of the follow-up period, there was an increase in ventilated FRCMBW and no change in plethysmographic FRCPL. This resulted in a significant decrease of trapped air by half a litre (from 579 to 40 ml; P = 0·013). Lung clearance index (LCI) also showed a small but significant decrease (from 7·2 to 6·7; P = 0·014) after eradication of MRSA. We conclude that MRSA eradication can be successful, also in terms of recruitment of previously unventilated air spaces, potentially due to reduced sputum production and/or viscosity.

ePS06.5 Burkholderia cepacia complex acquisition: A threat in all CF patients?

Introduction Acquisition of Burkholderia cepacia complex (Bcc) bacteria is considered to be associated with worsening of CF lung disease. Moreover, because of its resistance to antibiotics, Bcc is considered a threat in CF. Method Data from the Belgian CF Registry (year 2000–2010) were obtained. Inclusion: Bcc-infected patients with entries on lung function, BMI and days of IV treatment in at least 3 y after Bcc acquisition. For each case, we included 2 controls, matched for age at index year (year of first Bcc infection), pancreatic status, sex. FEV 1 , days of IV antibiotics and hospitalization were used as surrogates for disease burden. Cumulative data up to 2 y before index year were compared to values after infection using Rank sum test. Rate of decline in lung function was adjusted for baseline lung function, age, sex. Results Prevalence of Bcc in CF is low in Belgium ( B. multivorans. FEV1 at index year had lower tendency in the cases, however without significance. The number of days of IV treatment had higher tendency in the cases (p = ns). FEV1 decline after Bcc acquisition was comparable in cases and controls (–1.1%, SD = 0.5, vs –0.99%, SD = 0.4, p = 0.24). BMI slopes were also comparable between groups. Conclusion Our study suggests that Bcc infected patients are in no worse clinical condition and demonstrate no faster clinical deterioration compared to Bcc-uninfected patients. However, registry data are collected retrospectively and bear a risk of inaccuracy. Therefore, these results should be confirmed in a prospective, longitudinal study.

Nutritional status of children hospitalized for parapneumonic effusion

Background & Aims Among children hospitalized for pneumonia, those with parapneumonic effusion (PPE) are at particular risk for nutritional deterioration. This study aimed to 1) investigate the evolution of the nutritional status during hospitalization and at outpatient follow-up; 2) determine clinical risk factors for weight loss during hospitalization; 3) describe the nutritional interventions for these children. Methods Retrospective chart review (January ‘07 - September ‘12) of 56 children with pneumonia, complicated by PPE in two Belgian hospitals for data on body weight and height at admission (t0) and discharge (t1), and two weeks (t2) and one month (t3) after discharge. Length of hospitalization (LoS), length of stay in paediatric intensive care (LoSPICU) and maximal in-hospital weight loss (tmax) were calculated and nutritional interventions were recorded. Results The median (range) age was 3.5 (1.0–14.8) years. Weight or height was lacking in five (8.9%) children at t0 and in 28 (50%) at t1; 21.4% was weighed only once during hospitalization. At tmax, respectively 17/44 and 5/44 children lost ≥5% and ≥10% of their weight. Median (range) LoS and LoSPICU were 18.0 (10–41) and 4.0 (0–23) days. One-fourth received a nutritional intervention. Weight for height at admission (WFH(t0)) significantly predicted maximal weight loss (β (95% CI) = −0.34 (−2.0–−0.1); p = 0.03). At t2 and t3, 13/32 and 5/22 of the children with available follow-up data did not reach WFH(t0), whilst in 4/35 and 5/26 body weight remained ≥5% under the weight(t0). Conclusions One-third of children with pneumonia complicated by PPE and monitored for weight and height, lost ≥5% of their body weight during hospitalization. One-fourth did not reach initial WFH one month after discharge. Those with a higher WFH at admission were at higher risk of weight loss. More attention for monitoring of weight loss and the nutritional policy during and after hospitalization is warranted.

Emergence of livestock-associated MRSA isolated from cystic fibrosis patients: Result of a Belgian national survey

BACKGROUND This study aims to determine the prevalence and characteristics of Staphylococcus aureus in Belgian cystic fibrosis (CF) patients. METHODS Non-duplicate respiratory samples from 510 CF-patients (2012-2013) were examined. One isolate per patient was analysed unless different phenotypes were recovered. Isolates were investigated for mecA/mecC, toxins presence, spa-typing, MLST and SCCmec-typing. Potential livestock-associated (LA) isolates were examined for their immune-evasion-cluster (IEC) genes. RESULTS S. aureus (n = 380), including 41 small-colony variants (SCVs), were isolated from 66.7% patients. The prevalence of methicillin-resistant S. aureus (MRSA) colonization was 4.9%. Two MRSA isolates carried toxic shock syndrome toxin 1 (TSST-1). Most MRSA (65%) belonged to two nosocomial epidemic clones (CC5, CC8) widespread in Belgium. Methicillin susceptible S. aureus (MSSA) showed great genetic diversity. Five of 33 isolates belonging to potential LA-lineages were IEC negative, including three methicillin-resistant isolates, suggesting an animal origin. CONCLUSIONS The MRSA-prevalence in Belgian CF-patients remained constant (2001-2013), but SCV-prevalence increased. Most MRSA belonged to health-care-associated clones. Three patients carrying LA-MRSA were found, requiring further investigation to determine the risk factors for LA-MRSA acquisition.

67 CF patients with a declining FEV1: At risk for acquisition of Burkholderia cepacia complex infection?

Introduction Burkholderia cepacia complex (Bcc) infection is considered to be associated with worsening of CF lung disease. Patient to patient spread has been reported, however mechanisms of acquisition of Bcc are not well understood. Method: Data from the Belgian CF Registry (year 2000–2010) were collected. Inclusions: Bcc infected patients with entries on lung function in at least 1 y before and 3 y after Bcc acquisition. For each case, we included 2 controls, matched for age at the index year (year of first Bcc infection), pancreatic status, sex. Cumulative data up to 2 years before index year were compared to values obtained after infection using Rank sum test. Rate of decline in lung function was adjusted for baseline lung function, age, sex. Results Bcc prevalence in CF is low in Belgium (<3%). 183 patients were included: 61 cases, 122 controls. 59% were F508del homozygous. Mean age in cases was 20.9 y (SD 10.5) vs 20.3 y (SD 10.3) in controls. Among the Bcc, 54% were unspecified, 31% were B. multivorans. Mean FEV1 at index year was 65.2% (SD 24.9) in cases vs 73.1 (SD 26.9) in controls (p = 0.07). FEV1 decline before index year was significantly higher in cases (–1.7%, SD 0.5) compared to controls (–1.0%, SD 0.3) (p = 0.002). FEV1 slopes were comparable in the period after index year (–1.1%, SD 0.5, in cases vs –0.99%, SD 0.4, p = 0.24). Conclusion Our results suggest that a declining FEV1 precedes acquisition of Bcc and may be a risk factor. After acquisition, lung function decline was comparable in Bcc infected and uninfected patients. These results should be interpreted with caution, since registry data are collected retrospectively and bear a risk of incompleteness or inaccuracy.

105 Adaptation of Pseudomonas aeruginosa in the CF host: Link between laboratory findings and the clinic?

Objectives: Several highly transmissible and virulent genotypes of Pseudomonas aeruginosa have been recognised in the UK including the Liverpool, Midlands and Manchester genotypes and Clone C. It has been suggested that patients colonised with a transmissible genotype may have a poorer prognosis and increased treatment needs. We describe the clinical features of patients who isolated P. aeruginosa clone C in our paediatric CF centre. Methods: The hospital microbiology database was used to identify the patients. There were five isolations from five patients (four boys, aged 1−12 years, mean 4.4 years). All isolations were new, obtained from cough swabs performed at routine clinics. Four patients had new wet cough, one of whom had reduced lung function. One patient had no new clinical features. Four patients received intravenous antibiotics and one patient oral antibiotics. The organisms were sensitive to standard antipseudomonal antibiotics. The patients were removed from clinic and seen separately until confirmed negative for infection. Four patients remained free of infection in the one year following isolation. Three patients underwent bronchoscopy and BAL was culture negative. One patient had subsequent second isolation in the same year. The frequency of pre and post pseudomonas isolation respiratory exacerbations remains similar. All five are on conventional physiotherapy with no additional requirement of pharmacological treatment of chest disease. Conclusion: P. aeruginosa clone C isolates in our centre are currently sensitive to standard antibiotics. We have found no evidence of increased virulence or that the organism is overtly transmissible.