Azithromycin In Cystic Fibrosis Patients Research Articles

Azithromycin Exhibits Activity Against Pseudomonas aeruginosa in Chronic Rat Lung Infection Model.

Pseudomonas aeruginosa forms biofilms in the lungs of chronically infected cystic fibrosis patients, which are tolerant to both the treatment of antibiotics and the host immune system. Normally, antibiotics are less effective against bacteria growing in biofilms; azithromycin has shown a potent efficacy in cystic fibrosis patients chronically infected with P. aeruginosa and improved their lung function. The present study was conducted to evaluate the effect of azithromycin on P. aeruginosa biofilm. We show that azithromycin exhibited a potent activity against P. aeruginosa biofilm, and microscopic observation revealed that azithromycin substantially inhibited the formation of solid surface biofilms. Interestingly, we observed that azithromycin restricted P. aeruginosa biofilm formation by inhibiting the expression of pel genes, which has been previously shown to play an essential role in bacterial attachment to solid-surface biofilm. In a rat model of chronic P. aeruginosa lung infection, we show that azithromycin treatment resulted in the suppression of quorum sensing-regulated virulence factors, significantly improving the clearance of P. aeruginosa biofilms compared to that in the placebo control. We conclude that azithromycin attenuates P. aeruginosa biofilm formation, impairs its ability to produce extracellular biofilm matrix, and increases its sensitivity to the immune system, which may explain the clinical efficacy of azithromycin in cystic fibrosis patients.

Metabolomic Analysis by Nuclear Magnetic Resonance Spectroscopy as a New Approach to Understanding Inflammation and Monitoring of Pharmacological Therapy in Children and Young Adults With Cystic Fibrosis.

15-F2t-Isoprostane, a reliable biomarker of oxidative stress, has been found elevated in exhaled breath condensate (EBC), a non-invasive technique for sampling of airway secretions, in patients with cystic fibrosis (CF). Azithromycin has antioxidant properties in experimental models of CF, but its effects on oxidative stress in CF patients are largely unknown. Primary objective of this pilot, proof-of-concept, prospective, parallel group, pharmacological study, was investigating the potential antioxidant effects of azithromycin in CF patients as reflected by EBC 15-F2t-isoprostane. Secondary objectives included studying the effect of azithromycin on EBC and serum metabolic profiles, and on serum 15-F2t-isoprostane. In CF patients who were on maintenance treatment with oral vitamin E (200 UI once daily), treatment with oral azithromycin (250 or 500 mg depending on body weight) plus vitamin E (400 UI once daily) (group A) (n = 24) or oral vitamin E alone (400 UI once daily) (group B) (n = 21) was not associated with changes in EBC 15-F2t-isoprostane concentrations compared with baseline values after 8–weeks treatment or 2 weeks after treatment suspension. There was no between-group difference in post-treatment EBC 15-F2t-isoprostane. Likewise, no within- or between-group differences in serum 15-F2t-isoprostane concentrations were observed in either study group. NMR spectroscopy-based metabolomics of EBC shows that suspension of both azithromycin plus vitamin E and vitamin E alone has a striking effect on metabolic profiles in EBC. Between-group comparisons show that EBC metabolite distribution after treatment and 2 weeks after treatment suspension is different. Quantitative differences in ethanol, saturated fatty acids, acetate, acetoin/acetone, and methanol are responsible for these differences. Our study was unable to show antioxidant effect of azithromycin as add-on treatment with doubling the dose of oral vitamin E as reflected by 15-F2t-isoprostane concentrations in EBC. Add-on therapy with azithromycin itself does not induce EBC metabolite changes, but its suspension is associated with EBC metabolic profiles that are different from those observed after vitamin E suspension. The pathophysiological and therapeutic implications of these findings in patients with stable CF are unknown and require further research. Preliminary data suggest that EBC NMR-based metabolomics might be used for assessing the effects of pharmacological treatment suspension in stable CF patients.

130 Lack of association of meticillin-resistant Staphylococcus aureus and long term use of azithromycin in cystic fibrosis patients: a French cohort study

130 Lack of association of meticillin-resistant Staphylococcus aureus and long term use of azithromycin in cystic fibrosis patients: a French cohort study

Molecular characterization of macrolide resistance determinants [erm(B) and mef(A)] in Streptococcus pneumoniae and viridans group streptococci (VGS) isolated from adult patients with cystic fibrosis (CF)

Although long-term use of azithromycin has shown a significant clinical improvement for patients with cystic fibrosis (CF), its long-term effect on the susceptibility of commensal flora within CF airways has not yet been examined. We therefore suggest that long-term use of azithromycin increases macrolide resistance in commensal streptococci. Erythromycin susceptibility in naturally colonizing viridans group streptococci (VGS) was characterized, as well as macrolide resistance gene determinants through sequence analysis, in pneumococci (n = 15) and VGS [n = 84; i.e. Streptococcus salivarius (n = 30), Streptococcus mitis (n = 17), Streptococcus sanguinis (n = 11), Streptococcus oralis (n = 10), Streptococcus parasanguinis (n = 6), Streptococcus gordonii (n = 3), Streptococcus infantis (n = 3), Streptococcus cristatus (n = 2), Streptococcus anginosus (n = 1) and Streptococcus australis (n = 1)] isolated from sputum from 24 adult CF patients, who were on oral azithromycin therapy for at least the previous 7 months. Almost three-quarters of isolates (74; 74.7%) were resistant to erythromycin, whilst a further 15 (15.2%) had reduced susceptibility, leaving only 10 (10.1%) isolates susceptible to erythromycin. The majority (89.8%) were not susceptible to erythromycin, as demonstrated by possession of the erm(B) gene in 25/99 (25.3%), the mef(A) gene in 1/99 (1.0%), the mef(E) gene in 75/99 (75.8%) and both erm(B) and mef(E) genes simultaneously in 11/99 (11.1%). These results indicate that genotypic resistance for macrolides is common in VGS in adult CF patients, with efflux being over three times more frequent. Long-term treatment with azithromycin in CF patients may reduce antibiotic susceptibility in commensal VGS, where these organisms may potentially act as a reservoir of macrolide resistance determinants for newly acquired and antibiotic-susceptible pathogens.

Daily versus weekly azithromycin in cystic fibrosis patients

Daily versus weekly azithromycin in cystic fibrosis patients

Use of azithromycin in cystic fibrosis patients not infected with Pseudomonas aeruginosa

Use of azithromycin in cystic fibrosis patients not infected with Pseudomonas aeruginosa

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.

Clinical response to azithromycin in cystic fibrosis correlates with in vitro effects on Pseudomonas aeruginosa phenotypes

A 6-month clinical trial of azithromycin (AZM) in American cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infection showed clinical improvement without significant reduction in bacterial density. Sub-inhibitory AZM has been hypothesized to affect P. aeruginosa virulence, partly contributing to the mechanism of action of AZM. To correlate bacterial phenotypes of P. aeruginosa isolates with clinical response to AZM in CF patients. Pre-treatment P. aeruginosa isolates from subjects randomized to AZM in the US trial were characterized for bacterial phenotypes: AZM minimal inhibitory concentration (MIC), mucoidy, and baseline and AZM effects on twitching and swimming motility, and production of pyocyanin, protease and phospholipase C (PLC). Initial analyses of a subset of subjects identified phenotypes most strongly associated with FEV(1) response and pulmonary exacerbation. These phenotypes were subsequently characterized and tested in isolates from subjects of the complete AZM cohort. Exploratory analyses of the initial subset suggested that the MIC and in vitro change in PLC and swimming motility with AZM were the strongest candidates among the bacterial phenotypes. When tested, only the change in PLC was significantly correlated with the change in FEV(1) (P=0.05), and occurrence and time to pulmonary exacerbation (both P=0.02). In the complete cohort, change in PLC continued to show significant correlation with FEV(1) response (P=0.006), but not exacerbation. The in vitro effect of AZM on PLC correlates with FEV(1) response to AZM. This suggests that AZM anti-virulence effects may be predictive of clinical response and play a role in the mechanism of action of AZM in CF patients.

Macrolide resistance of Staphylococcus aureus and Haemophilus species associated with long-term azithromycin use in cystic fibrosis

Azithromycin is used to modulate exuberant inflammatory response in patients with cystic fibrosis (CF). The purpose of this study was to determine the association between long-term use of azithromycin in CF patients and change over time in macrolide susceptibility of Staphylococcus aureus and Haemophilus spp. The study was performed at the Erasmus MC-Sophia Children's Hospital. CF patients' sputum cultures were obtained at routine visits and at pulmonary exacerbations. All cultures between January 1999 and March 2004 were included. Antibiotic susceptibility of S. aureus and Haemophilus spp. was tested routinely. Susceptibility was compared with isolates from sputum of non-CF patients. Logistic regression was used to analyse the association between azithromycin use and resistance, adjusting for age, Pseudomonas carriage and time-trends. In March 2004 one-third of CF patients were on azithromycin maintenance treatment. S. aureus (715 isolates) and/or Haemophilus (537 isolates) were cultured in 141 of the 155 patients on one or more occasions. The study period was divided into octiles. Erythromycin resistance in S. aureus increased from 6.9 to 53.8% and clarithromycin resistance in Haemophilus spp. from 3.7 to 37.5%. Resistance but also isolation rates were strongly related to azithromycin use. Resistance of 3217 S. aureus control isolates remained stable and resistance of 3257 Haemophilus controls increased, although at a slower rate than CF isolates. Over a 4 year period, azithromycin maintenance therapy in our CF population was associated with an increase in macrolide resistance in S. aureus and Haemophilus spp.

Has the time come to prescribe azithromycin in cystic fibrosis patients?

Has the time come to prescribe azithromycin in cystic fibrosis patients?