Antimicrobial susceptibility and synergy studies of cystic fibrosis sputum by direct sputum sensitivity testing.

Standard disc diffusion antimicrobial susceptibility testing (C+S) on individual Pseudomonas aeruginosa colonial morphotypes cultured from cystic fibrosis (CF) sputum has questionable clinical relevance. Direct sputum sensitivity testing (DSST) is a whole-sputum susceptibility test that removes bias associated with selecting individual colonial morphotypes. We sought to determine whether, in principle, the results from DSST support the possibility of improved clinical relevance compared with C+S. Individual (DSSTi) and combination (DSST) susceptibility to gentamicin, tobramycin, ceftazidime and meropenem were determined on 130 sputum samples referred from CF subjects with antibiotic-resistant chronic Gram-negative endobronchial infection. DSSTi and concurrent C+S were compared for categorical susceptibility, synergistic combinations were evaluated and the combination DSST efficacy index (DEI) calculated. Meropenem and tobramycin were the most active individual antibiotics by DSSTi on 89 P. aeruginosa-predominant samples, with 62 % of samples sensitive to each. C+S and DSSTi showed poor agreement (κ ranging from 0.02 to 0.6), discordance ranging from 20 % (meropenem) to 49 % (tobramycin), with DSSTi demonstrating both increased susceptibility and increased resistance. The combination that most frequently had the highest DEI was tobramycin + meropenem, occurring in 76 % of samples. DSSTi appears to be reproducible, yields different antimicrobial susceptibility results from C+S without simply identifying the most resistant isolates and DSST identifies the most effective in vitro antibiotic combinations, providing preliminary proof of concept of the potentially improved clinical relevance of whole-sputum testing. Future studies will determine whether these potential theoretical advantages translate into clinical benefits.

Improvements in cystic fibrosis lung disease and airway inflammation associated with etanercept therapy for rheumatoid arthritis: a case report.

Cystic fibrosis (CF) lung pathology is characterized by excessive neutrophilic inflammation and high tumor necrosis factor-alpha (TNF-α) levels. A cornerstone of CF management is reduction of the inflammatory burden in the lung. We present the case of a 19-year-old CF patient who demonstrated significant clinical improvement in her lung disease associated with a reduction in sputum percent neutrophils, following commencement of etanercept (TNF-α antagonist) for rheumatoid arthritis. She has not had any infectious complications or other significant adverse effects during 2 years of treatment. It may be time to reconsider TNF-α antagonists as potential anti-inflammatory agents for CF lung disease.

Inhaled antibiotics for lower respiratory tract infections: focus on ciprofloxacin.

The administration of antibiotics by the inhaled route offers an appealing and logical approach to treating infectious respiratory conditions. Studies in the cystic fibrosis (CF) population have established the efficacy of this therapeutic concept and inhaled antibiotic therapy is now one of the pillars of management in CF. There are now a number of new inhaled antibiotic formulations that have shown impressive preliminary evidence for efficacy in CF and are commencing phase III efficacy studies. Translation of this paradigm into the non-CF bronchiectasis population has proven difficult thus far, apparently due to problems with tolerability of inhaled formulations. Inhaled versions of ciprofloxacin have shown good tolerability and microbiological efficacy in preliminary studies, suggesting that effective inhaled antibiotics are finally on the horizon for this previously neglected patient population. The increased use of long-term inhaled antibiotics for a wider range of non-CF indications presents risks to the broader community of greater antimicrobial resistance development that must be carefully weighed against any demonstrated benefits.

Long-term, low-dose erythromycin in bronchiectasis subjects with frequent infective exacerbations.

BACKGROUND: Macrolide antibiotics are increasingly prescribed for subjects with non-cystic fibrosis (CF) bronchiectasis, an empiric extension of their proven efficacy in CF. Widespread, injudicious use of long-acting macrolides, particularly azithromycin, risks significantly increasing population antimicrobial resistance. METHODS: In an attempt to power a definitive randomised-controlled trial (RCT), an uncontrolled evaluation of the impact of long-term, low-dose oral erythromycin therapy upon pulmonary exacerbation frequency in non-CF bronchiectasis subjects was performed. Adult bronchiectasis subjects with at least 2 infective exacerbations in the preceding 12 months were followed for 12 months following commencement of prophylactic oral erythromycin 250 mgs daily. The co-primary outcome measures, comparing the 12 month erythromycin and pre-erythomycin periods, were numbers of infective exacerbations and days of antibiotic therapy for infective exacerbations. RESULTS: In the 24 evaluable subjects completing a minimum of 12 months of therapy, erythromycin was associated with halving of both the median (range) annual number of infective exacerbations (2 (0-8) vs. 4 (2-11), 95% CI 1.5 to 3.5, p < 0.0001) and annual days of antibiotic use (21 (0-78) vs. 44 (15-138), 95% CI 18 to 40, p < 0.0001) compared with the preceding 12 month period. CONCLUSIONS: Low-dose erythromycin may have a robust effect upon exacerbation frequency in non-CF bronchiectasis subjects with frequent exacerbations and this warrants proceeding to a definitive intervention study. These data have enabled powering of an RCT of long-term, low-dose erythromycin, which is now underway and also incorporates bronchoscopic evaluation for pathophysiologic data.

Daily versus weekly azithromycin in cystic fibrosis patients.

Four randomised, placebo-controlled trials have previously documented the clinical benefits of azithromycin (AZM) in cystic fibrosis (CF) patients. The present study examined whether the beneficial effect of AZM is equivalent when administered daily or weekly. A double-blind, randomised study was carried out in 208 CF patients aged 6-58 yrs who were assigned to AZM either 250 mg daily (n = 103) or 1,200 mg weekly (n = 105) for 6 months, with assessments at baseline and at 1, 3, 6 and 7 months. Patients were taken from five adult and children CF centres in South-east Queensland, Australia. Equivalence was demonstrated between the two groups (daily versus weekly) with respect to improvements in lung function (forced expiratory volume in one second and forced vital capacity), C-reactive protein, days spent in hospital, admission rates and nutrition (body mass index, z-scores) using 95% confidence intervals with a tolerance interval of +/-10%. In patients aged <18 yrs the daily group had significantly better improvements in z-scores for height and weight after 6 months. In children, a nutritional advantage for daily administration was found. Gastro-intestinal adverse effects were more common with weekly therapy. Apart from these findings, daily and weekly administered azithromycin demonstrated similar outcomes for cystic fibrosis patients.

Use of 16S rRNA gene profiling by terminal restriction fragment length polymorphism analysis to compare bacterial communities in sputum and mouthwash samples from patients with cystic fibrosis.

The bacterial communities present in the oral cavity and the lungs of 19 adult cystic fibrosis (CF) patients were compared by using terminal restriction fragment length polymorphism analysis of 16S rRNA gene PCR products amplified from nucleic acids extracted directly from bacteria in clinical samples. Sputum samples were not found to be subject to profound contamination by oral cavity bacteria. Evidence of colonization of the CF lung by certain oral bacterial species was found.

Alveolar haemorrhage in anti-glomerular basement membrane disease without detectable antibodies by conventional assays.

Anti-glomerular basement membrane (anti-GBM) disease represents the spectrum of disease attributable to circulating anti-GBM antibodies. While active anti-GBM disease in the absence of circulating anti-GBM antibodies has been described, it is considered rare with the use of current routinely available assays. We report four subjects with features consistent with active anti-GBM antibody disease without detectable antibodies by routinely available enzyme linked immunosorbent assay (ELISA) and immunoblot techniques. All were smokers who presented with diffuse alveolar haemorrhage, minimal renal involvement, and undetectable anti-GBM antibodies. Seronegative anti-GBM disease with predominant pulmonary involvement may be more common than previously appreciated and should be part of the differential diagnosis for otherwise unexplained diffuse alveolar haemorrhage. Renal biopsy with immunofluorescent studies should be considered in the diagnostic evaluation of such subjects, including those with idiopathic pulmonary haemosiderosis.

Catheter-related thrombosis associated with elevated factor VIII levels in cystic fibrosis.

We report a cystic fibrosis (CF) subject with extensive, central venous catheter-associated thrombosis and sustained elevation of factor VIII to levels normally associated with significantly increased risks of deep venous thrombosis. To determine the potential significance of this finding, the prevalence of elevated factor VIII levels in 22 adults with CF was investigated. Mean (S.D.) factor VIII level was 177 (43) U/dl, with 77% of subjects having levels >150 U/dl. The high prevalence of elevated factor VIII levels questions the significance of this finding in CF subjects with catheter-related thrombosis.

Inhaled heparin in cystic fibrosis.

Cystic fibrosis (CF) is characterised by inspissated airway secretions and chronic endobronchial infection associated with exuberant neutrophilic inflammation. Unfractionated heparin may be mucolytic and has demonstrated a number of anti-inflammatory properties; however, further safety data are needed in these subjects who are at risk of airway bleeding. The current study aimed to assess the medium-term safety and tolerability of moderately high-dose inhaled heparin in CF adults and to explore possible in vivo mucolytic and anti-inflammatory outcomes. A randomised, double-blind, placebo-controlled crossover study of twice daily inhalation of 50,000 IU of heparin for 2 weeks was undertaken in CF adults, with a 1-week washout period. Eighteen subjects were randomised and 14 (mean+/-sd age 23+/-7.8 yrs and percentage-predicted forced expiratory volume in one second 52.1+/-15.56%) completed the study protocol. Heparin neither affected blood coagulation parameters nor resulted in any increase in adverse events. Heparin inhalation had no significant effect upon forced expiratory volume in one second, symptoms of sputum clearance or sputum inflammatory markers. The current pilot study demonstrated no evidence of improved sputum clearance with 50,000 IU of inhaled heparin given twice daily to adult cystic fibrosis subjects. However, inhaled heparin was safe and the future evaluation of larger doses over a longer period may be warranted.

Resolution of trigeminal neuralgia following third ventriculostomy for hydrocephalus associated with Chiari I malformation: case report.

OBJECTIVE AND IMPORTANCE: Cranial nerve dysfunction, including trigeminal neuralgia, has been associated with Chiari I malformations. In such cases, trigeminal neuralgia is thought to be related to tonsillar compression of the brainstem or to traction on the cranial nerves. Hydrocephalus may be a contributing factor. CLINICAL PRESENTATION: A 38-year-old woman had right-sided lancinating facial pain typical of trigeminal neuralgia but was otherwise neurologically intact. Magnetic resonance imaging showed no evidence of a compressing vessel. Moderate hydrocephalus and a Chiari I malformation were noted incidentally. The visibility of the aqueduct was poor. INTERVENTION: The patient underwent a third ventriculostomy and her symptoms resolved completely. CONCLUSION: This is the first case in which trigeminal neuralgia was treated with a third ventriculostomy and one of only four cases of isolated trigeminal neuralgia associated with a Chiari malformation. Acquired aqueductal stenosis may have caused the hydrocephalus which, in turn, caused the Chiari malformation configuration that caused the trigeminal neuralgia. The rationale for the treatment modality and possible causes of Chiari I-induced trigeminal neuralgia are discussed.

characterization of bacterial community diversity in cystic fibrosis lung infections by use of 16s ribosomal DNA terminal restriction fragment length polymorphism profiling.

Progressive loss of lung function resulting from the inflammatory response to bacterial colonization is the leading cause of mortality in cystic fibrosis (CF) patients. A greater understanding of these bacterial infections is needed to improve lung disease management. As culture-based diagnoses are associated with fundamental drawbacks, we used terminal restriction fragment (T-RF) length polymorphism profiling and 16S rRNA clone data to characterize, without prior cultivation, the bacterial community in 71 sputa from 34 adult CF patients. Nineteen species from 15 genera were identified in 53 16S rRNA clones from three patients. Of these, 15 species have not previously been reported in CF lung infections and many were species requiring strict anaerobic conditions for growth. The species richness and evenness were determined from the T-RF length and volume for the 71 profiles. Species richness was on average 13.3 +/- 7.9 per sample and 13.4 +/- 6.7 per patient. On average, the T-RF bands of the lowest and highest volumes represented 0.6 and 59.2% of the total volume in each profile, respectively. The second through fifth most dominant T-RF bands represented 15.3, 7.5, 4.7, and 2.8% of the total profile volume, respectively. On average, the remaining T-RF bands represented 10.2% of the total profile volume. The T-RF band corresponding to Pseudomonas aeruginosa had the highest volume in 61.1% of the samples. However, 18 other T-RF band lengths were dominant in at least one sample. In conclusion, this reveals the enormous complexity of bacteria within the CF lung. Although their significance is yet to be determined, these findings alter our perception of CF lung infections.