J. M. Wolter

Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial

Background: Relentless chronic pulmonary inflammation is the major contributor to morbidity and mortality in patients with cystic fibrosis (CF). While immunomodulating therapies such as prednisolone and ibuprofen may be beneficial, their use is limited by side effects. Macrolides have immunomodulatory properties and long term use dramatically improves prognosis in diffuse panbronchiolitis, a condition with features in common with the lung disease of CF. Methods: To determine if azithromycin (AZM) improves clinical parameters and reduces inflammation in patients with CF, a 3 month prospective randomised double blind, placebo controlled study of AZM (250 mg/day) was undertaken in adults with CF. Monthly assessment included lung function, weight, and quality of life (QOL). Blood and sputum collection assessed systemic inflammation and changes in bacterial flora. Respiratory exacerbations were treated according to the policy of the CF Unit. Results: Sixty patients were recruited (29 men) of mean (SD) age 27.9 (6.5) years and initial forced expiratory volume in 1 second (FEV1) 56.6 (22.3)% predicted. FEV1% and forced vital capacity (FVC)% predicted were maintained in the AZM group while in the placebo group there was a mean (SE) decline of –3.62 (1.78)% (p=0.047) and –5.73 (1.66)% (p=0.001), respectively. Fewer courses of intravenous antibiotics were used in patients on AZM (0.37 v 1.13, p=0.016). Median C reactive protein (CRP) levels declined in the AZM group from 10 to 5.4 mg/ml but remained constant in the placebo group (p<0.001). QOL improved over time in patients on AZM and remained unchanged in those on placebo (p=0.035). Conclusion: AZM in adults with CF significantly improved QOL, reduced CRP levels and the number of respiratory exacerbations, and reduced the rate of decline in lung function. Long term AZM may have a significant impact on morbidity and mortality in patients with CF. Further studies are required to define frequency of dosing and duration of benefit.

Mannose-binding lectin gene polymorphism predicts hospital admissions for COPD infections

Infection frequently causes exacerbations of chronic obstructive pulmonary disease (COPD). Mannose-binding lectin (MBL) is a pattern-recognition receptor that assists in clearing microorganisms. Polymorphisms in the MBL2 gene reduce serum MBL levels and are associated with risk of infection. We studied whether the MBL2 codon 54 B allele affected serum MBL levels, admissions for infective exacerbation in COPD and disease susceptibility. Polymorphism frequency was determined by PCR-RFLP in 200 COPD patients and 104 smokers with normal lung function. Serum MBL was measured as mannan-binding activity in a subgroup of 82 stable COPD patients. Frequency of COPD admissions for infective exacerbation was ascertained for a 2-year period. The MBL2 codon 54 B allele reduced serum MBL in COPD patients. In keeping, patients carrying the low MBL-producing B allele had increased risk of admission for infective exacerbation (OR 4.9, Pcorrected=0.011). No association of MBL2 genotype with susceptibility to COPD was detected. In COPD, serum MBL is regulated by polymorphism at codon 54 in its encoding gene. Low MBL-producing genotypes were associated with more frequent admissions to hospital with respiratory infection, suggesting that the MBL2 gene is disease-modifying in COPD. MBL2 genotype should be explored prospectively as a prognostic marker for infection risk in COPD.

A randomised trial of home vs hospital intravenous antibiotic therapy in adults with infectious diseases

OBJECTIVE Despite widespread adoption of home care services, few randomised trials have compared health outcomes in the hospital and at home. We report a prospective, randomised trial of home versus hospital therapy in adults receiving intravenous (IV) antibiotics. Our objective was to show that home care is a feasible alternative to hospitalisation over a broad range of infections, without compromise to quality of life (QOL) or clinical outcomes. METHODS Consenting adults requiring IV antibiotics were randomised to complete therapy at home or in hospital. Short Form 36 and Perceived Health Competence Scale (PHCS) were used for assessment of QOL. Statistical analysis used unpaired t-tests, Mann-Whitney tests and ANOVA. RESULTS One hundred and twenty-nine admissions were referred. Recruitment was hampered by patient preference for one therapy over another. 82 (62%) were included and randomised: 44 to home, 38 to hospital; the two groups had comparable characteristics. There were no differences in improvements in QOL and PHCS scores between the two groups after treatment. Treatment duration was median 11.5 days (range 3-57) and 11 days (range 4-126) for home and hospital groups, respectively. Home therapy costs, approximately, half that of hospital therapy. Time to readmission was longer after hospital therapy. CONCLUSION Out study showed that home IV therapy is well tolerated, is less costly, is not associated with any major disadvantage to QOL or clinical outcomes compared to hospital therapy, and is an appropriate treatment option for selected patients.

Macrolides in cystic fibrosis: is there a role?

A spectrum of anti-inflammatory properties, evidence of anti-infective action against Pseudomonas aeruginosa at sub-inhibitory concentrations and positive clinical experience in patients with diffuse panbronchiolitis, a disease with features in common with cystic fibrosis (CF), has prompted research to evaluate the role of macrolide therapy in patients with CF. Newer macrolides such as azithromycin have the advantage of improved tolerability and a prolonged intracellular half-life requiring an infrequent dosing regimen.Results from initial studies suggest a benefit from several months of macrolide therapy in patients with CF. An improvement in lung function was initially shown in a small open study in children, while maintenance of lung function compared with placebo, reduced acute respiratory exacerbations, and reduced systemic markers of inflammation were demonstrated in a randomized, placebo-controlled study of macrolide therapy in adult patients with CF.Additional controlled studies are required to determine optimal drug, dosage, and duration of therapy, and long-term adverse effects of prolonged therapy with macrolides in patients with CF. The potential, with long-term use, to induce resistance against other bacteria colonizing the upper respiratory tract e.g. pneumococci has not been explored.Measurement of cytokines and inflammatory mediators from the sputum of patients with CF is technically difficult and does not correlate with disease activity. There is a need for easily measurable, reproducible and clinically meaningful end-points for evaluation of new therapies in CF. The choice of appropriate outcome measures, apart from lung function, to monitor disease activity needs careful consideration in clinical trials determining the efficacy of macrolides in patients with CF.Evidence-based recommendations for the use of macrolides in the treatment of CF are not expected for some years although macrolides are already being prescribed for long-term use in some centers. There is a need for further research into mechanisms of anti-inflammatory action of macrolides in the lungs of patients with CF and whether or not such therapy may be beneficial in the long term.

The Effect of Subinhibitory Concentrations of Antibiotics on Adherence of Pseudomonas aeruginosa to Cystic Fibrosis (CF) and Non-CF-affected Tracheal Epithelial Cells

OBJECTIVES this project investigated the proposition that Pseudomonas aeruginosa binds preferentially to cystic fibrosis (CF) respiratory cells. In addition, disadherence of P. aeruginosa by subinhibitory concentrations of antibiotics was examined as a possible explanation for clinical improvement seen in chronically colonized patients when treated with anti-pseudomonal agents. METHODS we used a distinctive HPV-transformed respiratory cell line to compare adherence of two strains of P. aeruginosa to CF and non-CF respiratory cells. The effect of subinhibitory concentrations of antipseudomonal antibiotics on adherence of P. aeruginosa to cell monolayers was measured. RESULTS piliated P. aeruginosa bound significantly better to CF than non-CF-affected cells (P=0.003). Adherence was significantly reduced when organisms were preincubated in subinhibitory concentrations of antibiotics overnight (P<0.001). CONCLUSIONS these results support the presence of an altered receptor present on CF-affected cells that binds piliated strains of P. aeruginosa. Bacterial disadherence due to subinhibitory concentrations of antibiotics may partially explain why clinical improvement is observed in CF patients with acute respiratory exacerbations.

Long-term treatment with azithromycin results in reduced in vitro inflammatory cytokine production in adults with cystic fibrosis

Induced transcripts ID RefSeq Symbol Description GB51383 LOC550965 probable Cytochrom P450 6a14 GB40836 LOC100576126 uncharacterized LOC100576126 GB41097 LOC724565 trypsin-7 GB41306 LOC551369 actin, clone 205-like GB42514 GB43892 LOC551401 cytosolic 10-formyltetrahydrofolate dehydrogenase GB46197 LOC726277 anaphase-promoting complex subunit CDC26-like GB50989 GB51146 LOC102655756 PDZ and LIM domain protein 7-like GB51218 LOC107964586 uncharacterized LOC107964586 GB54099

Effect of antibiotics on neutrophil elastase (NE) activity in cystic fibrosis

The Australasian Society for Infectious Diseases (ASID) Inc. is an independent organisation, founded in Melbourne in 1976 by an eminent group of physicians, pathologists and scientists. Membership encompasses Infectious Diseases Physicians, Clinical Microbiologists, Scientists, Infection Control Practitioners, Public Health Physicians, Sexual Health Physicians, Veterinarians and others eminent in the field of infectious diseases.