zithromax and Cystic-Fibrosis

Respiratory tract infections with Pseudomonas aeruginosa occur in most people with cystic fibrosis (CF). Established chronic P aeruginosa infection is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate. This is an updated review.. Does giving antibiotics for P aeruginosa infection in people with CF at the time of new isolation improve clinical outcomes (e.g. mortality, quality of life and morbidity), eradicate P aeruginosa infection, and delay the onset of chronic infection, but without adverse effects, compared to usual treatment or an alternative antibiotic regimen? We also assessed cost-effectiveness.. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and conference proceedings. Latest search: 24 March 2022. We searched ongoing trials registries. Latest search: 6 April 2022.. We included randomised controlled trials (RCTs) of people with CF, in whom P aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous (IV) antibiotics with placebo, usual treatment or other antibiotic combinations. We excluded non-randomised trials and cross-over trials.. Two authors independently selected trials, assessed risk of bias and extracted data. We assessed the certainty of the evidence using GRADE.. We included 11 trials (1449 participants) lasting between 28 days and 27 months; some had few participants and most had relatively short follow-up periods. Antibiotics in this review are: oral - ciprofloxacin and azithromycin; inhaled - tobramycin nebuliser solution for inhalation (TNS), aztreonam lysine (AZLI) and colistin; IV - ceftazidime and tobramycin. There was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment. Two trials were supported by the manufacturers of the antibiotic used. TNS versus placebo TNS may improve eradication; fewer participants were still positive for P aeruginosa at one month (odds ratio (OR) 0.06, 95% confidence interval (CI) 0.02 to 0.18; 3 trials, 89 participants; low-certainty evidence) and two months (OR 0.15, 95% CI 0.03 to 0.65; 2 trials, 38 participants). We are uncertain whether the odds of a positive culture decrease at 12 months (OR 0.02, 95% CI 0.00 to 0.67; 1 trial, 12 participants). TNS (28 days) versus TNS (56 days) One trial (88 participants) comparing 28 days to 56 days TNS treatment found duration of treatment may make little or no difference in time to next isolation (hazard ratio (HR) 0.81, 95% CI 0.37 to 1.76; low-certainty evidence). Cycled TNS versus culture-based TNS One trial (304 children, one to 12 years old) compared cycled TNS to culture-based therapy and also ciprofloxacin to placebo. We found moderate-certainty evidence of an effect favouring cycled TNS therapy (OR 0.51, 95% CI 0.31 to 0.82), although the trial publication reported age-adjusted OR and no difference between groups. Ciprofloxacin versus placebo added to cycled and culture-based TNS therapy One trial (296 participants) examined the effect of adding ciprofloxacin versus placebo to cycled and culture-based TNS therapy. There is probably no difference between ciprofloxacin and placebo in eradicating P aeruginosa (OR 0.89, 95% CI 0.55 to 1.44; moderate-certainty evidence). Ciprofloxacin and colistin versus TNS We are uncertain whether there is any difference between groups in eradication of P aeruginosa at up to six months (OR 0.43, 95% CI 0.15 to 1.23; 1 trial, 58 participants) or up to 24 months (OR 0.76, 95% CI 0.24 to 2.42; 1 trial, 47 participants); there was a low rate of short-term eradication in both groups. Ciprofloxacin plus colistin versus ciprofloxacin plus TNS One trial (223 participants) found there may be no difference in positive respiratory cul. We found that nebulised antibiotics, alone or with oral antibiotics, were better than no treatment for early infection with P aeruginosa. Eradication may be sustained in the short term. There is insufficient evidence to determine whether these antibiotic strategies decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of P aeruginosa. One large trial showed that intravenous ceftazidime with tobramycin is not superior to oral ciprofloxacin when inhaled antibiotics are also used. There is still insufficient evidence to state which antibiotic strategy should be used for the eradication of early P aeruginosa infection in CF, but there is now evidence that intravenous therapy is not superior to oral antibiotics.

Topics: Anti-Bacterial Agents; Azithromycin; Ceftazidime; Child; Child, Preschool; Ciprofloxacin; Colistin; Cystic Fibrosis; Humans; Infant; Monobactams; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Azithromycin (AZM), sold under the name Zithromax, is classified as a macrolide. It has many benefits due to its immunomodulatory, anti-inflammatory, and antibacterial effects. This review aims to study different clinical and biochemisterial aspects and properties of this drug which has a priority based on literature published worldwide.. Several databases including Web of Science, Google Scholar, PubMed, and Scopus were searched to obtain the relevant studies.. AZM mechanism of action including the inhibition of bacterial protein synthesis, inhibition of proinflammatory cytokine production, inhibition of neutrophil infestation, and macrophage polarization alteration, gives it the ability to act against a wide range of microorganisms. Resistant organisms are spreading and being developed because of the irrational use of the drug in the case of dose and duration. AZM shows synergistic effects with other drugs against a variety of organisms. This macrolide is considered a valuable antimicrobial agent because of its use as a treatment for a vast range of diseases such as asthma, bronchiolitis, COPD, cystic fibrosis, enteric infections, STIs, and periodontal infections.. Our study shows an increasing global prevalence of AZM resistance. Thus, synergistic combinations are recommended to treat different pathogens. Moreover, continuous monitoring of AZM resistance by registry centers and the development of more rapid diagnostic assays are urgently needed.

Topics: Anti-Bacterial Agents; Azithromycin; Bacterial Proteins; Cystic Fibrosis; Humans

Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport and subsequent airway surface liquid dehydration that severely compromise the airway microenvironment. Noxious agents and pathogens are entrapped inside the abnormally thick mucus layer and establish a highly inflammatory environment, ultimately leading to lung damage. Since chronic airway inflammation plays a crucial role in CF pathophysiology, several studies have investigated the mechanisms responsible for the altered inflammatory/immune response that, in turn, exacerbates the epithelial dysfunction and infection susceptibility in CF patients. In this review, we address the evidence for a critical role of dysfunctional inflammation in lung damage in CF and discuss current therapeutic approaches targeting this condition, as well as potential new treatments that have been developed recently. Traditional therapeutic strategies have shown several limitations and limited clinical benefits. Therefore, many efforts have been made to develop alternative treatments and novel therapeutic approaches, and recent findings have identified new molecules as potential anti-inflammatory agents that may exert beneficial effects in CF patients. Furthermore, the potential anti-inflammatory properties of CFTR modulators, a class of drugs that directly target the molecular defect of CF, also will be critically reviewed. Finally, we also will discuss the possible impact of SARS-CoV-2 infection on CF patients, with a major focus on the consequences that the viral infection could have on the persistent inflammation in these patients.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Cannabinoids; COVID-19; COVID-19 Drug Treatment; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Eicosanoids; Humans; Inflammation; Protein Kinase Inhibitors; Roscovitine; Signal Transduction; Thymalfasin

The first clinical indication of non-antibiotic benefits of macrolides was in the Far East, in adults with diffuse panbronchiolitis. This condition is characterised by chronic airway infection, often with Pseudomonas aeruginosa, airway inflammation, bronchiectasis and a high mortality. Low dose erythromycin, and subsequently other macrolides, led in many cases to complete remission of the condition, and abrogated the neutrophilic airway inflammation characteristic of the disease. This dramatic finding sparked a flurry of interest in the many hundreds of macrolides in nature, especially their anti-inflammatory and immunomodulatory effects. The biggest subsequent trials of azithromycin were in cystic fibrosis, which has obvious similarities to diffuse panbronchiolitis. There were unquestionable improvements in lung function and pulmonary exacerbations, but compared to diffuse panbronchiolitis, the results were disappointing. Case reports, case series and some randomised controlled trials followed in other conditions. Three trials of azithromycin in preschool wheeze gave contradictory results; a trial in pauci-inflammatory adult asthma, and a trial in non-cystic fibrosis bronchiectasis both showed a significant reduction in exacerbations, but none matched the dramatic results in diffuse panbronchiolitis. There is clearly a huge risk of antibacterial resistance if macrolides are used widely and uncritically in the community. In summary, Azithromycin is not the answer to anything in paediatric respiratory medicine; the paediatric respiratory community needs to refocus on the dramatic benefits of macrolides in diffuse panbronchiolitis, use modern - omics technologies to determine the endotypes of inflammatory diseases and discover in nature or synthesise designer macrolides to replicate the diffuse panbronchiolitis results. We must now find out how to do better!

Topics: Anti-Bacterial Agents; Asthma; Azithromycin; Bronchiectasis; Bronchiolitis; Bronchiolitis Obliterans; Bronchiolitis, Viral; Child; Child, Preschool; Ciliary Motility Disorders; Cystic Fibrosis; Disease Progression; Drug Resistance, Bacterial; Haemophilus Infections; Humans; Infant; Lung Diseases, Interstitial; Lung Transplantation; Macrolides; Respiratory Sounds; Stem Cell Transplantation

The evidence base for modulator therapies in cystic fibrosis (CF) has continued to expand, and it is likely that up to 90% of people with CF could benefit. Worldwide there are however marked inequalities of access to basic CF care and modulator therapies. For infants and young children there is now an evidence base for inhaled hypertonic saline. There is increasing evidence that structural lung disease in CF is not due purely to infection and that mucus retention and inflammation are also key, and further evidence of the value of azithromycin in those chronically infected with Pseudomonas aeruginosa. Finally, exercise is good for you, but airway clearance is better for mucus clearance.

Topics: Administration, Inhalation; Aminophenols; Aminopyridines; Anti-Bacterial Agents; Azithromycin; Benzodioxoles; Carrier State; Chloride Channel Agonists; Cystic Fibrosis; Drug Combinations; Exercise; Health Services Accessibility; Healthcare Disparities; Humans; Indoles; Inflammation; Physical Therapy Modalities; Pseudomonas Infections; Pyrazoles; Pyridines; Quinolines; Quinolones; Saline Solution, Hypertonic

This paper reviews the most important clinical papers in cystic fibrosis published in 2018, having searched all the literature on Pubmed. Focus is on CFTR modulator therapy, randomised controlled trials, and infection/microbiology issues.

Topics: Administration, Inhalation; Aminophenols; Aminopyridines; Anti-Bacterial Agents; Azithromycin; Benzodioxoles; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Chloride Channel Agonists; Cough; Cross Infection; Cystic Fibrosis; Disease Progression; Drug Combinations; Drug Therapy, Combination; Humans; Indoles; Lung Transplantation; Microbiological Techniques; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Nebulizers and Vaporizers; Proton Pump Inhibitors; Pseudomonas aeruginosa; Pseudomonas Infections; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Randomized Controlled Trials as Topic; Saline Solution, Hypertonic; Specimen Handling; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

Macrolide agents have both antibacterial properties as well as various effects on the inflammatory system. In recent years there is growing evidence regarding the favourable effects of macrolides in a range of chronic respiratory conditions. Historically, erythromycin and clarithromycin were found to stabilize pulmonary deterioration in diffuse panbronchiolitis. In cystic fibrosis patients colonized with pseudomonas aeruginosa, long term treatment with azithromycin reduces exacerbations and presents improved lung function. A similar effect on prevention of exacerbations has been demonstrated in noncystic fibrosis bronchiectasis. In patients undergoing lung transplantation, long term azithromycin prevents bronchiolitis obliterans syndrome. In patients with chronic obstructive pulmonary disease (COPD), azithromycin prevents acute exacerbations. Chronic treatment with macrolides is associated with adverse effects including gastrointestinal symptoms, interactions with other drugs and cardiovascular complications. Of the macrolides, azithromycin is associated with the lowest interactions and adverse effects and is also the most investigated.

Topics: Anti-Bacterial Agents; Azithromycin; Clarithromycin; Cystic Fibrosis; Erythromycin; Humans; Lung Diseases; Macrolides

Mycobacterium abscessus is an emerging mycobacteria that is responsible for lung diseases and healthcare-associated extrapulmonary infections. Recent findings support its taxonomic status as a single species comprising 3 subspecies designated abscessus, bolletii and massiliense. We performed a review of English-language publications investigating all three of these subspecies. Areas covered: Worldwide, human infections are often attributable to environmental contamination, although the isolation of M. abscessus in this reservoir is very rare. Basic research has demonstrated an association between virulence and cell wall components and cording, and genome analysis has identified gene transfer from other bacteria. The bacteriological diagnosis of M. abscessus is based on innovative tools combining molecular biology and mass spectrometry. Genotypic and phenotypic susceptibility testing are required to predict the success of macrolide (clarithromycin or azithromycin)-based therapeutic regimens. Genotyping methods are helpful to assess relapse and cross-transmission and to search for a common source. Treatment is not standardised, and outcomes are often unsatisfactory. Expert commentary: M. abscessus is still an open field in terms of clinical and bacteriological research. Further knowledge of its ecology and transmission routes, as well as host-pathogen interactions, is required. Because the number of human cases is increasing, it is also necessary to identify more active treatments and perform clinical trials to assess standard effective regimens.

Topics: Anti-Bacterial Agents; Azithromycin; Clarithromycin; Cystic Fibrosis; Humans; Mycobacterium; Mycobacterium Infections; Prevalence; Respiratory Tract Infections; Treatment Outcome; Virulence

Systemic antibiotic treatment is established for many pulmonary diseases, e.g., cystic fibrosis (CF), bronchiectasis and chronic obstructive pulmonary disease (COPD) where recurrent bacterial infections cause a progressive decline in lung function. In the last decades inhalative administration of antibiotics was introduced into clinical routine, especially tobramycin, colistin, and aztreonam for treatment of CF and bronchiectasis. Even though they are important in systemic treatment of these diseases due to their antimicrobial spectrum and anti-inflammatory and immunomodulatory properties, macrolides (e.g., azithromycin, clarithromycin, erythromycin, and telithromycin) up to now are not administered by inhalation. The number of in vitro aerosol studies and in vivo inhalation studies is also sparse. We analyzed publications on preparation and administration of macrolide aerosols available in PUBMED focusing on recent publications. Studies with solutions and dry powder aerosols were published. Publications investigating physicochemical properties of aerosols demonstrated that macrolide aerosols may serve for inhalation and will achieve sufficient lung deposition and that the bitter taste can be masked. In vivo studies in rats demonstrated high concentrations and areas under the curve sufficient for antimicrobial treatment in alveolar macrophages and epithelial lining fluid without lung toxicity. The obtained data demonstrate the feasibility of macrolide inhalation which should be further investigated.

Topics: Administration, Inhalation; Aerosols; Animals; Anti-Bacterial Agents; Azithromycin; Bronchiectasis; Clarithromycin; Cystic Fibrosis; Erythromycin; Humans; Ketolides; Lung; Macrolides; Pulmonary Disease, Chronic Obstructive; Rats

Rational antimicrobial administration is still considered to be the most effective therapeutic approach in cystic fibrosis (CF), and long-term treatment with azithromycin (Az) is included in the current guidelines for CF patients aged ≥ 6 years. Az has microbiological, immunomodulatory and anti-inflammatory properties that can reduce some of the biological problems that are among the causes of the progressive lung damage associated with CF. Moreover, although it is not active against Pseudomonas aeruginosa (the most important bacterial pathogen responsible for infectious exacerbations), it can be efficiently used in the case of P. aeruginosa infections because sub-inhibitory concentrations can reduce their pathogenic role by interfering with some bacterial activities and increasing their susceptibility to antibiotics. Az also has anti-viral activity that limits the risk of the bacterial pulmonary exacerbations that frequently occur after apparently mild viral infections. The available data seem to indicate that it is effective during its first year of administration, but the impact of longer treatment is debated. Other still undefined aspects of the use of Az include the possible emergence of antibiotic resistance in the other bacterial pathogens that usually colonise CF patients, the real incidence of adverse events and the drug's potential interference with other routine therapies.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchopneumonia; Cystic Fibrosis; Humans; Pneumonia, Bacterial

To propose a formalized consensus agreement regarding the prescription of azithromycin in cystic fibrosis (CF).. Application of the Delphi method in 5 thematic fields: indications, contra-indications, dosage, precautions for use and treatment follow-up.. Thirty identified French CF centers participated in the process on 49 (61%), which comprised 3 rounds. Experts validated azithromycin as a long-term anti-inflammatory agent in children aged over 6 years, presenting with the classical form of CF, irrespective of the bacteriological status of the patient (except for non-tuberculous mycobacteria). Azithromycin administration should not be routine in the milder forms of the disease, and avoided in the presence of severe hepatic or renal involvement. In children whose weight is below 40 kg, a strong consensus recommended a single daily oral dose, administered three times weekly. However, in adults, the level of agreement was weaker. Minimal duration of treatment is 6 months, after which the drug should be discontinued if no observable effect is noted on clinical parameters, exacerbation rate and/or FEV1. Clinical monitoring of treatment tolerance is recommended (nausea, diarrhea, skin rash, tinnitus, deafness, arthropathy), without increasing the frequency of surveillance of sputum bacteria. However, it is essential to monitor sputum for fungi (expectoration, Aspergillus, broncho-pulmonary allergic aspergillosis).. This consensus statement defines an area for the prescription of azithromycin in CF, with the aim of better harmonization of its use.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Child; Consensus; Cystic Fibrosis; France; Humans; Opportunistic Infections; Practice Guidelines as Topic; Young Adult

Randomized, controlled trials have demonstrated that chronic therapy with macrolide antibiotics reduces the morbidity of patients with cystic fibrosis, non-cystic fibrosis bronchiectasis, chronic obstructive pulmonary disease, and nontuberculous mycobacterial infections. Lower levels of evidence indicate that chronic macrolides are also effective in treating patients with panbronchiolitis, bronchiolitis obliterans, and rejection after lung transplant. Macrolides are known to cause torsade des pointes and other ventricular arrhythmias, and a recent observational study prompted the FDA to strengthen the Warnings and Precautions section of azithromycin drug labels. This summary describes the electrophysiological effects of macrolides, reviews literature indicating that the large majority of subjects experiencing cardiac arrhythmias from macrolides have coexisting risk factors and that the incidence of arrhythmias in absence of coexisting risk factors is very low, examines recently published studies describing the relative risk of arrhythmias from macrolides, and concludes that this risk has been overestimated and suggests an approach to patient evaluation that should reduce the relative risk and the incidence of arrhythmias to the point that chronic macrolides can be used safely in the majority of subjects for whom they are recommended.

Topics: Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Cystic Fibrosis; Heart Conduction System; Humans; Macrolides; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Factors

Mycobacterium abscessus is the most common rapidly growing mycobacterium that causes lung disease. This review describes recently published literature regarding M. abscessus taxonomy, environmental niche, diagnosis, management and outcome in pulmonary disease in adults and adolescents with cystic fibrosis.. The classification of M. abscessus subsp. abscessus, M. abscessus subsp. massiliense and M. abscessus subsp. bolletii is useful clinically because of the discovery of the erm(41) gene, which is responsible for macrolide resistance in M. abscessus. Macrolide susceptibility is key for successful treatment of M. abscessus subsp. massiliense. The poor outcome and eradication of M. abscessus subsp. abscessus remains both a diagnostic and treatment challenge in approximately 80% of isolates that are macrolide resistant. Molecular studies, such as genotyping, may allow prediction of disease progression. Overall, there is a dearth of new literature surrounding M. abscessus.. New studies differentiating M. abscessus subsp. abscessus and M. abscessus subsp. massiliense based on the erm(41) gene demonstrate the latter to have a better prognosis and improved treatment outcomes. M. abscessus subsp. abscessus remains a formidable pathogen in diagnosis and treatment.

Topics: Adolescent; Adult; Amikacin; Anti-Bacterial Agents; Antibiotics, Antitubercular; Azithromycin; Cystic Fibrosis; DNA-Binding Proteins; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Genotype; Humans; Molecular Diagnostic Techniques; Molecular Sequence Data; Mycobacterium Infections, Nontuberculous; Polymorphism, Single Nucleotide; Respiratory Tract Infections; Sequence Analysis, DNA; Transcription Factors; Treatment Outcome

Azithromycin maintenance therapy results in improvement of respiratory function in patients with cystic fibrosis (CF). In azithromycin maintenance therapy, several dosing schemes are applied. In this review, we combine current knowledge about azithromycin pharmacokinetics with the dosing schedules used in clinical trials in order to come to a dosing advise which could be generally applicable. We used data from a recently updated Cochrane meta analysis (2011), the reports of clinical trials and pharmacokinetic studies. Based on these data, it was concluded that a dose level of 22-30 mg/kg/week is the lowest dose level with proven efficacy. Due to the extended half-life in patients with CF, the weekly dose of azithromycin can be divided in one to seven dosing moments, depending on patient preference and gastro-intestinal tolerance. No important side effects or interactions with other CF-related drugs have been documented so far.

Topics: Anti-Bacterial Agents; Azithromycin; Clinical Trials as Topic; Cystic Fibrosis; Humans; Meta-Analysis as Topic; Pneumonia, Bacterial

Macrolide antibiotics may have a modifying role in diseases which involve airway infection and inflammation, like cystic fibrosis.. To test the hypotheses that, in people with cystic fibrosis, macrolide antibiotics: 1. improve clinical status compared to placebo or another antibiotic; 2. do not have unacceptable adverse effects. If benefit was demonstrated, we aimed to assess the optimal type, dose and duration of macrolide therapy.. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings.We contacted investigators known to work in the field, previous authors and pharmaceutical companies manufacturing macrolide antibiotics for unpublished or follow-up data (May 2010).Latest search of the Group's Cystic Fibrosis Trials Register: 29 February 2012.. Randomised controlled trials of macrolide antibiotics compared to: placebo; another class of antibiotic; another macrolide antibiotic; or the same macrolide antibiotic at a different dose.. Two authors independently extracted data and assessed risk of bias. Seven groups were contacted and provided additional data which were incorporated into the review.. Ten of 31 studies identified were included (959 patients). Five studies with a low risk of bias examined azithromycin versus placebo and demonstrated consistent improvement in forced expiratory volume in one second over six months (mean difference at six months 3.97% (95% confidence interval 1.74% to 6.19%; n = 549, from four studies)). Patients treated with azithromycin were approximately twice as likely to be free of pulmonary exacerbation at six months, odds ratio 1.96 (95% confidence interval 1.15 to 3.33). With respect to secondary outcomes, there was a significant reduction in need for oral antibiotics and greater weight gain in those taking azithromycin. Adverse events were uncommon and not obviously associated with azithromycin, although a once-weekly high dose regimen was associated with more frequent gastrointestinal adverse events. Treatment with azithromycin was associated with reduced identification of Staphylococcus aureus on respiratory culture, but also a significant increase in macrolide resistance.. This review provides evidence of improved respiratory function after six months of azithromycin. Data beyond six months were less clear, although reduction in pulmonary exacerbation was sustained. Treatment appeared safe over a six-month period; however, emergence of macrolide resistance was a concern. A multi-centre trial examining long-term effects of this antibiotic treatment is needed, especially for infants recognised through newborn screening.

Topics: Anti-Bacterial Agents; Azithromycin; Bacterial Infections; Cystic Fibrosis; Disease Progression; Humans; Macrolides; Outcome Assessment, Health Care; Pseudomonas aeruginosa; Pseudomonas Infections; Randomized Controlled Trials as Topic

To evaluate the efficacy and safety of macrolides in cystic fibrosis (CF).. Randomized controlled trials (RCTs) of macrolides for the treatment of CF published in PubMed, the Cochrane Library and Embase were searched. Application of inclusion and exclusion criteria, data extraction, and assessment of methodological quality were independently performed in duplicate. The primary efficacy outcome was the impact on the deterioration of lung function (changes in FEV(1) and FVC). Safety outcomes included adverse events and mortality.. Eight RCTs (seven with azithromycin and one with clarithromycin) were found in the systematic review and six RCTs with azithromycin (654 patients) were included in the meta-analysis. Azithromycin treatment showed a significant increase in FEV(1)% (3.22%, 95% CI = 1.38-5.06, P = 0.0006, I(2) = 0%) and FVC% (3.23%, 95% CI = 1.62-4.85, P < 0.0001, I(2) = 0%) compared with placebo. In individuals with baseline Pseudomonas aeruginosa colonization, both FEV(1)% (4.80%, 95% CI = 1.66-7.94, P = 0.003, I(2) = 42%) and FVC% (4.74%, 95% CI = 1.92-7.57, P = 0.001, I(2) = 0%) increased significantly. The incidence rates of the main side effects (cough, headache, abdominal pain, vomiting, nausea and diarrhoea) were not significantly different between the azithromycin-treated group and the placebo group. The RCT of clarithromycin, involving 18 patients, showed its effects on clinical improvement; however, the small sample size made comparisons with azithromycin difficult.. Long-term use of azithromycin can improve lung function, especially for P. aeruginosa-colonized CF patients. There was no evidence of increased adverse events with azithromycin. More data are needed to verify the best azithromycin regimen and to evaluate other macrolides in CF patients.

Topics: Anti-Bacterial Agents; Azithromycin; Clarithromycin; Cystic Fibrosis; Humans; Lung; Macrolides; Pneumonia, Bacterial; Randomized Controlled Trials as Topic; Respiratory Function Tests; Treatment Outcome

Antibiotics have significant role in the treatment of respiratory diseases. The main aim of their use is to treat infection, but anti-inflammatory properties of macrolides are also beneficial in selected diseases. The role of antibiotics in the therapy of asthma exacerbation can be neglected and should be limited to exceptional situations of bacterial infections which are very rare. During last few years the role of atypical infections in asthma inception, induction of exacerbation and modification of chronic course of disease has been discussed. Antibiotics play significant role in cystic fibrosis therapy. They are especially recommended during exacerbation, when new pathogens are revealed and in chronic Pseudomonas aeruginosa infection. This paper includes the principal rules of antibiotics therapy in patients with cystic fibrosis. The role of azithromycin in antiinflammatory therapy in this group of patients is also presented.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Asthma; Azithromycin; Child; Cystic Fibrosis; Humans; Respiratory Tract Infections

Macrolide antibiotics may have a modifying role in diseases which involve airway infection and inflammation, like cystic fibrosis.. To test the hypotheses that, in people with cystic fibrosis, macrolide antibiotics: 1. improve clinical status compared to placebo or another antibiotic; 2. do not have unacceptable adverse effects. If benefit was demonstrated, we aimed to assess the optimal type, dose and duration of macrolide therapy.. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings.We contacted investigators known to work in the field, previous authors and pharmaceutical companies manufacturing macrolide antibiotics for unpublished or follow-up data (May 2010).Latest search of the Group's Cystic Fibrosis Trials Register: 09 February 2011.. Randomised controlled trials of macrolide antibiotics compared to: placebo; another class of antibiotic; another macrolide antibiotic; or the same macrolide antibiotic at a different dose.. Two authors independently extracted data and assessed risk of bias. Seven groups were contacted and provided additional data which were incorporated into the review.. Ten of 31 studies identified were included (959 patients). Five studies with a low risk of bias examined azithromycin versus placebo and demonstrated consistent improvement in forced expiratory volume in one second over six months (mean difference at six months 3.97% (95% confidence interval 1.74% to 6.19%; n = 549, from four studies)). Patients treated with azithromycin were approximately twice as likely to be free of pulmonary exacerbation at six months, odds ratio 1.96 (95% confidence interval 1.15 to 3.33). With respect to secondary outcomes, there was a significant reduction in need for oral antibiotics and greater weight gain in those taking azithromycin. Adverse events were uncommon and not obviously associated with azithromycin, although a once-weekly high dose regimen was associated with more frequent gastrointestinal adverse events. Treatment with azithromycin was associated with reduced identification of Staphylococcus aureus on respiratory culture, but also a significant increase in macrolide resistance.. This review provides evidence of improved respiratory function after six months of azithromycin. Data beyond six months were less clear, although reduction in pulmonary exacerbation was sustained. Treatment appeared safe over a six-month period; however, emergence of macrolide resistance was a concern. A multi-centre trial examining long-term effects of this antibiotic treatment is needed, especially for infants recognised through newborn screening.

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Disease Progression; Humans; Macrolides; Outcome Assessment, Health Care; Pseudomonas aeruginosa; Pseudomonas Infections; Randomized Controlled Trials as Topic

Interest in azithromycin in the management of patients with cystic fibrosis has grown over the last decade. Uniquely this drug has both antibacterial and immune modulating effects which appear to be the reason for its clinical benefit as proven in several well designed clinical studies. In this review we discuss the proposed mechanisms of action of azithromycin and review the evidence for its clinical effectiveness and safety in cystic fibrosis.

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Humans

Azithromycin has been studied as potential therapeutic anti-inflammatory agent for cystic fibrosis (CF) patients. Azithromycin (AZM) has been used as an immunomodulating agent, based on few small studies. Considering the cost and potential side effects of long-term azithromycin therapy, it is important to identify the group of patients that would benefit the most. Weighted mean difference was used for pulmonary function tests, and risk ratios for all other variables. The random-effects model was applied for all reports. Combining four studies (N=368), azithromycin showed increase in FEV(1) (3.53%, 95% CI 0.00, 7.07, p=0.05; I(2)=38%) and FVC (4.24%, 95% CI 2.02, 6.45, p=0.0002; I(2)=0%). When trials were analyzed by baseline Pseudomonas sputum colonization, the heterogeneity decreased (I(2)=0%), FEV(1) significantly increased to 4.66% (95% CI 1.18, 8.15, p=0.009), and FVC increased to 4.64% (95% CI 2.11, 7.17, p=0.0003). The GI side effects were 72% higher with azithromycin use (RR 1.72, 95% CI 1.33, 2.21, p=0.00003), the main side effects being nausea (RR 2.04, 95% CI 1.19, 3.45, p=0.009), and diarrhea (RR 2.12, 95% CI 1.10, 4.08, p=0.02). Azithromycin improves lung function of CF patients, especially in the subgroup colonized with Pseudomonas. However, nausea and diarrhea are significantly more frequent with azythromycin.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Biomarkers; Child; Cystic Fibrosis; Female; Humans; Inflammation; Male; Publication Bias; Quality of Life; Respiratory Function Tests; Treatment Outcome; Vital Capacity; Young Adult

Pseudomonas aeruginosa is an opportunistic pathogen of immunocompromised hosts. In cystic fibrosis (CF), P. aeruginosa causes acute and chronic lung infections that result in significant morbidity and mortality. P. aeruginosa possesses several traits that contribute to its ability to colonize and persist in acute and chronic infections. These include high resistance to antimicrobials, ability to form biofilms, plethora of virulence products, and metabolic versatility. In P. aeruginosa, a cell-to-cell communication process termed quorum sensing (QS) regulates many of these factors that contribute to its pathogenesis. Recent evidence suggests that the CF lung environment presents a specialized niche for P. aeruginosa. The relationship of P. aeruginosa QS, biofilm formation, and the CF lung environment is discussed.

Topics: Animals; Azithromycin; Biofilms; Cystic Fibrosis; DNA, Bacterial; Gene Expression Regulation, Bacterial; Humans; Immunity, Mucosal; Immunocompromised Host; Lung; Opportunistic Infections; Pseudomonas aeruginosa; Pseudomonas Infections; Quorum Sensing; Tobramycin

Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability worldwide. The Global Burden of Disease study has concluded that COPD will become the third leading cause of death worldwide by 2020, and will increase its ranking of disability-adjusted life years lost from 12th to 5th. Acute exacerbations of COPD (AECOPD) are associated with impaired quality of life and pulmonary function. More frequent or severe AECOPDs have been associated with especially markedly impaired quality of life and a greater longitudinal loss of pulmonary function. COPD and AECOPDs are characterized by an augmented inflammatory response. Macrolide antibiotics are macrocyclical lactones that provide adequate coverage for the most frequently identified pathogens in AECOPD and have been generally included in published guidelines for AECOPD management. In addition, they exert broad-ranging, immunomodulatory effects both in vitro and in vivo, as well as diverse actions that suppress microbial virulence factors. Macrolide antibiotics have been used to successfully treat a number of chronic, inflammatory lung disorders including diffuse panbronchiolitis, asthma, noncystic fibrosis associated bronchiectasis, and cystic fibrosis. Data in COPD patients have been limited and contradictory but the majority hint to a potential clinical and biological effect. Additional, prospective, controlled data are required to define any potential treatment effect, the nature of this effect, and the role of bronchiectasis, baseline colonization, and other cormorbidities.

Topics: Anti-Bacterial Agents; Asthma; Azithromycin; Bronchiectasis; Bronchiolitis; Cystic Fibrosis; Disease Progression; Humans; Macrolides; Pulmonary Disease, Chronic Obstructive; Quality of Life

Cystic fibrosis is the most common incurable hereditary disease in the US. Persistent respiratory infection is the leading cause of morbidity and mortality in cystic fibrosis patients.. This study aimed to review the literature on economic and quality of life outcomes and treatment compliance associated with antibiotic therapies for cystic fibrosis patients.. A systematic literature review was conducted using keyword searches of the MEDLINE database and selected conference abstracts. The review covered studies published between January 1990 and May 2007.. Evidence suggests that inhaled tobramycin, a key chronic suppressive therapy, can reduce other healthcare costs. The main determinants of the cost of care include disease severity and respiratory infection. Costs vary widely by country. There is evidence that inhaled tobramycin and oral azithromycin improve quality of life and that treatment setting and patient convenience may also impact on quality of life. Antibiotic treatment compliance varied significantly and depended on the method of measurement, with more subjective measures tending to be higher. This review concludes by offering directions for future research.

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Health Care Costs; Humans; Patient Compliance; Quality of Life; Respiratory Tract Infections; Severity of Illness Index; Tobramycin

Mycobacterium abscessus is the most pathogenic and chemotherapy-resistant rapid-growing mycobacterium. It is commonly associated with contaminated traumatic skin wounds and with post-surgical soft tissue infections. It is also one of the mycobacteria that are most often isolated from cystic fibrosis patients. It is essential to differentiate this species from the formerly indistinct "M. chelonae-complex", as chemotherapy is especially difficult in M. abscessussenso strictu. Clarithromycin or azithromycin are the only regular oral antimycobacterial agents with an effect on M. abscessus, and should preferably be supplemented with other drugs since long-term monotherapy may cause resistance. Amikacin is a major parenteral drug against M. abscessus that should also be given in combination with another drug. The recently introduced drug tigecycline may prove to be an important addition to chemotherapy, but has yet to be fully clinically evaluated as an antimycobacterial agent. Surgery can be curative, or at least helpful, in the healing of M. abscessus infection, and if conducted, it should include the removal of all foreign or necrotic material. There is increasing awareness of M. abscessus as an emerging pathogen.

Topics: Administration, Oral; Amikacin; Anti-Bacterial Agents; Azithromycin; Clarithromycin; Cystic Fibrosis; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Microbial Sensitivity Tests; Minocycline; Mycobacterium; Mycobacterium Infections; Respiratory Tract Infections; Skin; Soft Tissue Infections; Species Specificity; Surgical Wound Infection; Tigecycline; Tuberculosis, Cutaneous; Wounds and Injuries

Long-term low dose azithromycin treatment in cystic fibrosis patients with chronic Pseudomonas aeruginosa infection is safe and reduces the decline in lung function, the number of acute exacerbations and improves nutritional status; underlying efficacy mechanisms are multiple and synergistic.

Topics: Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Humans; Pseudomonas Infections

Topics: Anti-Infective Agents; Asthma; Azithromycin; Bronchiolitis; Chronic Disease; Clinical Trials as Topic; Cystic Fibrosis; Erythromycin; Gene Expression Regulation, Bacterial; Humans; Macrolides; Mucins; Neutrophils; Pancreatic Elastase; Pseudomonas aeruginosa; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Sinusitis; Structure-Activity Relationship

Inflammation is a major component of the vicious cycle characterizing cystic fibrosis pulmonary disease. If untreated, this inflammatory process irreversibly damages the airways, leading to bronchiectasis and ultimately respiratory failure. Antiinflammatory drugs for cystic fibrosis lung disease appear to have beneficial effects on disease parameters. These agents include oral corticosteroids and ibuprofen, as well as azithromycin, which, in addition to its antimicrobial effects, also possesses antiinflammatory properties. Inhaled corticosteroids, colchicine, methotrexate, montelukast, pentoxifylline, nutritional supplements, and protease replacement have not had a significant impact on the disease. Therapy with oral corticosteroids, ibuprofen, and fish oil is limited by adverse effects. Azithromycin appears to be safe and effective, and is thus the most promising antiinflammatory therapy available for patients with cystic fibrosis. Pharmacologic therapy with antiinflammatory agents should be started early in the disease course, before extensive irreversible lung damage has occurred.

Topics: Acetates; Administration, Inhalation; Administration, Oral; Adult; Anti-Inflammatory Agents; Azithromycin; Child; Clinical Trials as Topic; Cyclopropanes; Cystic Fibrosis; Deoxyribonuclease I; Dietary Supplements; Humans; Methotrexate; Pentoxifylline; Quinolines; Sulfides

Inflammation plays a major role in the pathophysiology of lung disease in CF. This response is probably triggered primarily as a reaction to the inability of the affected lung to resist the invasion of the most common bacterial pathogens seen in this disease, namely, Staphylococcus aureus, Haemophilus influenzae and Pseudomonas aeruginosa. Debate continues as to whether there may or may not be a pre-inflammation of the lungs as part of the basic functional defect of CFTR. The anti-inflammatory treatment modalities most tested to date are: oral corticosteroids, effective but associated with significant long-term side effects, inhaled corticosteroids, so far not proven to be effective probably because of difficulty with absorption through the viscid surface secretions of the lung and ibuprofen, potentially effective but inhibited by the need to monitor drug levels invasively and potential gastrointestinal side effects. The most promising newcomer is macrolide antibiotics such as azithromycin acting as a long-term anti-inflammatory agent with an excellent safety profile.

Topics: Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Azithromycin; Cystic Fibrosis; Humans; Ibuprofen; Immunoglobulins; Macrolides

For more than 20 years macrolide antibiotics have been used to treat chronic inflammatory airway diseases based on their immunomodulatory activity. Macrolide antibiotics down-regulate damaging prolonged inflammation as well as increase mucus clearance, decrease bacterial virulence and prevent biofilm formation. Initially shown to decrease morbidity and mortality in diffuse panbronchiolitis and in steroid-dependent asthma, long-term macrolide therapy has now been shown to significantly reduce exacerbations and improve lung function and quality of life in children with cystic fibrosis. They have also proven beneficial in Japanese children and adults with chronic sinobronchitis especially when there is nasal polyposis. Long-term macrolides have also proven clinically beneficial in some patients with plastic bronchitis. Adverse reactions are few and generally self-limited when used at the recommended dosage for immunomodulation.

Topics: Anti-Bacterial Agents; Asthma; Azithromycin; Bronchitis; Child; Clarithromycin; Cystic Fibrosis; Drug Resistance; Humans; Inflammation; Macrolides; Respiratory Tract Diseases

Azithromycin is a macrolide antibiotic that has been structurally modified from erythromycin with an expanded spectrum of activity and improved tissue pharmacokinetic characteristics relative to erythromycin. This allows once-daily administration for 3-5 days of treatment compared with traditional multi dosing 7-10-day treatment regimens. It has been successfully employed in lower respiratory tract infections. Recent data indicate that azithromycin may exert anti-inflammatory/immunomodulatory effects that may be of use in the treatment of both acute and chronic airway diseases. This review examines the role of azithromycin in lower respiratory tract infections analysing published data on exacerbations of chronic bronchitis, community-acquired pneumonia and cystic fibrosis both in adults and children. In addition, pharmacokinetic and pharmacodynamic properties of the drug are also considered.

Topics: Adult; Aged; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Bronchitis, Chronic; Child; Community-Acquired Infections; Cystic Fibrosis; Drug Administration Schedule; Drug Resistance, Bacterial; Haemophilus influenzae; Humans; Multicenter Studies as Topic; Pneumonia, Bacterial; Pseudomonas aeruginosa; Randomized Controlled Trials as Topic; Respiratory Tract Infections; Streptococcus pneumoniae

The discovery of the clinical effectiveness of erythromycin and azithromycin in inflammatory airway diseases has inspired the discovery and development of macrolides with selective immunomodulatory activity. Erythromycin degradation continues to be a source of novel macrolides with a variety of selective biological activities. New technologies for drug discovery based in the emerging field of combinatorial biosynthesis provide the medicinal chemist with novel approaches toward the discovery of novel macrolides. Recent efforts to integrate synthetic organic medicinal chemistry with combinatorial biosynthesis have expanded the number of techniques available for macrolide synthesis.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Combinatorial Chemistry Techniques; Cystic Fibrosis; Drug Design; Erythromycin; Humans; Immunologic Factors; Inflammation; Macrolides

Progressive lung disease, caused by chronic endobronchial colonization, is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Several pathogens, including Staphylococcus aureus and Pseudomonas aeruginosa are responsible for this effect. The steadily improving prognosis of CF has been attributed to the use of antibiotics with activity against these organisms. Despite a significant increase in the amount of published material demonstrating the potential role of macrolide antibiotics as antiinflammatory agents and their effects on bacterial virulence, their mechanism of action in CF patients is still unknown. Although there is a limited number of clinical trials assessing the efficacy and safety of azithromycin (AZM) in CF, increasing evidence suggests that 3 to 6-month AZM treatment in CF patients is safe and well tolerated. This treatment results in clinical improvement, decreasing the number of pulmonary exacerbations and increasing pulmonary function. Therefore, chronic treatment with AZM should be considered in CF patients added to conventional therapy. Clinical experience with macrolides other than AZM in CF patients is very limited.

Topics: Anti-Bacterial Agents; Azithromycin; Clinical Trials as Topic; Cystic Fibrosis; Humans; Pneumonia, Bacterial

To review the literature concerning the use of azithromycin in the treatment of patients with cystic fibrosis (CF).. A search of MEDLINE (1966-April 2004), Embase (1980-April 2004), and International Pharmaceutical Abstracts (1971-April 2004) was performed. Search terms included cystic fibrosis, macrolide, and azithromycin.. Four studies have been performed in 7-185 patients (children and adults) over a 3- to 6-month period. The azithromycin dosage ranged from 250 mg 3 times weekly to 500 mg daily. The trials reported an improvement in percent predicted forced expiratory volume ranging from 2.95% to 6.2% in patients treated with azithromycin compared with those receiving placebo.. Azithromycin appeared to improve pulmonary function in adults and older children with CF and was well tolerated when administered for 6 months. Further research is needed to determine an optimal dosage regimen, duration of treatment, effects on quality of life, and cost-effectiveness of azithromycin therapy.

Topics: Anti-Bacterial Agents; Azithromycin; Clinical Trials as Topic; Cystic Fibrosis; Humans; Lung; Pseudomonas aeruginosa; Pseudomonas Infections

There has been much recent interest in the use of macrolide antibiotics as chronic suppressive therapy in patients with cystic fibrosis. Three recent randomized, placebo-controlled trials have been conducted.. All three trials used similar regimens of azithromycin, and lung function improved after 3 to 6 months of treatment. The relative change in forced expiratory volume in 1 second predicted improved between 3.6% and 6.2%. Furthermore, the azithromycin treatment groups had improvement in a variety of secondary outcomes related to pulmonary exacerbations, including a reduction in antibiotic use (both intravenous and oral) and hospitalization rate. Furthermore, azithromycin was well tolerated: Only nausea, diarrhea, and wheezing (described as mild to moderate) occurred more frequently in the azithromycin group compared with the placebo group. The evidence for the clinical benefit of azithromycin in cystic fibrosis has been summarized in a Cochrane review in which a meta-analysis confirmed a significant improvement in forced expiratory volume in 1 second among the 286 pooled participants.. Azithromycin has entered the therapeutic armamentarium for patients with cystic fibrosis who are chronically infected with Pseudomonas aeruginosa. Improved lung function, a reduction in pulmonary exacerbations and antibiotic use, and weight gain are potential benefits of this drug. Future studies should address the use of azithromycin in other cystic fibrosis patient populations, including those patients without chronic infection with P. aeruginosa, children younger than 6 years of age, and those infected with Burkholderia cepacia complex. The mechanism of action of macrolide antibiotics in cystic fibrosis remains unknown.

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Forced Expiratory Volume; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Randomized Controlled Trials as Topic

During what is a relatively barren time for new therapies for cystic fibrosis (CF), azithromycin has received a lot of attention as a potential treatment for CF lung disease. Laboratory studies suggest that azithromycin may have indirect actions, including anti-inflammatory, in addition to the standard antibacterial properties. The unique pharmacokinetics of azithromycin sets it aside from other macrolide antibiotics, but may result in increased resistance patterns. Three well-designed randomised controlled trials have demonstrated a small but significant improvement in respiratory function (forced expiratory volume in one second) with azithromycin compared with placebo. These trial results are confirmed by a recent meta-analysis. Mild adverse events (wheeze, diarrhoea and nausea) were significantly increased in one trial. There is no clear consensus regarding the correct dose and length of treatment with azithromycin. The present review discusses the role of azithromycin in the management of cystic fibrosis and the need for close monitoring of patients started on this drug. In addition, clinics should liaise closely with their microbiology departments and monitor resistance patterns.

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Drug Resistance, Bacterial; Humans; Randomized Controlled Trials as Topic

Cystic fibrosis (CF) is an autosomal-recessive disorder that predominantly affects the respiratory system. When this disease was described in 1938 the mortality rate was approximately 70 % in the first year of life. Survival has dramatically increased from a median of approximately 4 years in the 1960s to 19 years in the 1970s and 33 years in 2001 according to figures from the American Cystic Fibrosis Foundation. This impressive increase in the life expectancy of individuals with CF is undoubtedly related to recent advances in the organization of specialized CF units and to the use of new therapies against respiratory involvement.The traditional basis of treatment for CF lung disease includes nutritional support, antibiotic therapy, chest physical therapy and aerobic exercise. Preventive measures such as influenza vaccination and avoidance of tobacco smoke are also useful. Several new approaches such as ion transport therapy, protein therapy and gene therapy are currently being developed. Many studies have provided clear evidence of the therapeutic benefits of antibiotics, respiratory physiotherapy, exercise, and nutrition. In this article we review the scientific evidence on the advantages of the use of several therapeutic interventions against inflammation, increased sputum viscoelasticity and adhesiveness, and bronchial obstruction in CF patients.

Topics: Azithromycin; Bronchodilator Agents; Child; Complementary Therapies; Cystic Fibrosis; Deoxyribonucleases; Glucocorticoids; Humans; Ibuprofen; Practice Guidelines as Topic

This summary of the current knowledge of macrolide therapy serves as an example of recent progress in the therapeutic approach to treating patients with cystic fibrosis (CF). The benefit of macrolides in the treatment of patients with diffuse panbronchiolitis and Pseudomonas aeruginosa infections, as seen in Japan, was the rational behind trials in patients with CF. Thus far, the majority of reports of positive trends in the therapeutic potential of macrolides have studied azithromycin. The data presented in peer reviewed journals are, however, too sparse to already justify firm recommendations for the general use of azithromycin, erythromycin or clarithromycin on a long-term basis for the treatment of chronic lung disease in CF.

Topics: Anti-Bacterial Agents; Azithromycin; Clarithromycin; Clinical Trials as Topic; Cystic Fibrosis; Erythromycin; Humans; Randomized Controlled Trials as Topic

Cystic fibrosis lung inflammation is early, sustained and severe and would justify an anti-inflammatory treatment. At present, the inhaled corticosteroid treatment did not give evidence of efficacy, contrary to the oral presentation, but at the cost of side effects. Azithromycin gives more encouraging results with a good tolerance. New molecules are in the process of validation.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Cystic Fibrosis; Humans; Inflammation

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.

Topics: Azithromycin; Cystic Fibrosis; Humans; Macrolides; Randomized Controlled Trials as Topic; Respiratory Function Tests

Cystic fibrosis affects 1/2500 individuals and is the most common lethal autosomal recessive disease in people of northern European descent. It is characterized by chronic infections with mucoid Pseudomonas aeruginosa and progressive deterioration of respiratory function. Much research has focused on the inflammatory component of the disease. Macrolide antibiotics are postulated to suppress inflammatory mediators and interfere with biofilm formation produced by P. aeruginosa. In vitro studies show promising results, and a limited number of human studies reported improvements in respiratory function with the drugs. Macrolide antibiotics are generally safe and well tolerated and may prove to be effective in patients with cystic fibrosis.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Clarithromycin; Clinical Trials as Topic; Cystic Fibrosis; Erythromycin; Humans; Inflammation; Molecular Structure; Pseudomonas aeruginosa

Following evidence from randomized controlled trials, patients with bronchiectasis unrelated to cystic fibrosis receive long-term azithromycin to reduce acute respiratory exacerbations. However, the period when azithromycin is effective and which patients are likely to most benefit remain unknown.. (i) What is the period after its commencement when azithromycin is most effective? and (ii) Which factors may modify azithromycin effects?. A secondary analysis was conducted of our previous randomized controlled trial involving 89 indigenous children with bronchiectasis unrelated to cystic fibrosis. Semi-parametric Poisson regression identified the azithromycin efficacy period. Multivariable Poisson regression identified factors that modify azithromycin effect.. Azithromycin was associated with fewer exacerbations per child-week during weeks 4 through 96, with the most effective period observed between weeks 17 and 62. Eleven factors were associated with different azithromycin effects; four were significant at the P < .05 level. Compared with their counterparts, higher reduction in exacerbations was observed in children with nasopharyngeal carriage of bacterial pathogens (incidence rate ratio [IRR] = 0.81 [95% CI, 0.57-1.14] vs 0.29 [0.20-0.44]; P < .001); New Zealand children (IRR = 0.73 [0.51-1.03] vs 0.39 [0.28-0.55]; P = .012); and those with higher weight-for-height z scores (interaction IRR = 0.82 [0.67-0.99]; P = .044). Compared with their counterparts, lower reduction was observed in those born preterm (IRR = 0.41 [0.30-0.55] vs 0.74 [0.49-1.10]; P = .012).. Regular azithromycin is best used for at least 17 weeks and up to 62 weeks, as these periods provide maximum benefit for indigenous children with bronchiectasis unrelated to cystic fibrosis. Several factors modified azithromycin benefits; however, these traits need confirmation in larger studies before being adopted into clinical practice.. Australian New Zealand Clinical Trials Registry; ACTRN12610000383066.

Topics: Anti-Bacterial Agents; Australia; Azithromycin; Bronchiectasis; Cystic Fibrosis; Double-Blind Method; Humans; Infant, Newborn

Cystic Fibrosis (CF) is a genetic condition characterized by neutrophilic inflammation and recurrent infection of the airways. How these processes are initiated and perpetuated in CF remains largely unknown. We have demonstrated a link between the intestinal microbiota-related metabolites bile acids (BA) and inflammation in the bronchoalveolar lavage fluid (BALF) from children with stable CF lung disease. To establish if BA indicate early pathological processes in CF lung disease, we combined targeted mass spectrometry and amplicon sequencing-based microbial characterization of 121 BALF specimens collected from 12-month old infants with CF enrolled in the COMBAT-CF study, a multicentre randomized placebo-controlled clinical trial comparing azithromycin versus placebo. We evaluated whether detection of BA in BALF is associated with the establishment of the inflammatory and microbial landscape of early CF lung disease, and whether azithromycin, a motilin agonist that has been demonstrated to reduce aspiration of gastric contents, alters the odds of detecting BA in BALF. We also explored how different prophylactic antibiotics regimens impact the early life BALF microbiota.. Detection of BA in BALF was strongly associated with biomarkers of airway inflammation, more exacerbation episodes during the first year of life, increased use of oral antibiotics with prolonged treatment periods, a higher degree of structural lung damage, and distinct microbial profiles. Treatment with azithromycin, a motilin agonist, which has been reported to reduce aspiration of gastric contents, did not reduce the odds of detecting BA in BALF. Culture and molecular methods showed that azithromycin does not alter bacterial load or diversity in BALF. Conversely, penicillin-type prophylaxis reduced the odds of detecting BAs in BALF, which was associated with elevated levels of circulating biomarkers of cholestasis. We also observed that environmental factors such as penicillin-type prophylaxis or BAs detection were linked to distinct early microbial communities of the CF airways, which were associated with different inflammatory landscapes but not with structural lung damage.. Detection of BA in BALF portend early pathological events in CF lung disease. Benefits early in life associated with azithromycin are not linked to its antimicrobial properties. Video Abstract.

Topics: Anti-Bacterial Agents; Azithromycin; Bile Acids and Salts; Bronchoalveolar Lavage Fluid; Cystic Fibrosis; Humans; Infant; Inflammation; Motilin; Penicillins

Inhaled tobramycin and oral azithromycin are common chronic therapies in people with cystic fibrosis and. A 6-week prospective, randomised, placebo-controlled, double-blind trial testing oral azithromycin versus placebo combined with clinically prescribed inhaled tobramycin in individuals with cystic fibrosis and. Despite having greater reduction in

Topics: Administration, Inhalation; Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Forced Expiratory Volume; Humans; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Chronic azithromycin improves outcomes in cystic fibrosis (CF), but its mechanism of action is unclear. The OPTIMIZE trial demonstrated improvement in time to first pulmonary exacerbation in children with new Pseudomonas treated with azithromycin. Azithromycin effect on systemic markers of inflammation over 18 months was assessed by change from baseline for high-sensitivity C-reactive protein, myeloperoxidase, calprotectin and absolute neutrophil count in the OPTIMIZE population. Subjects treated with chronic azithromycin or placebo had samples collected at baseline, 39 and 78 weeks of treatment. In 129 subjects, a significant decrease in high-sensitivity C-reactive protein was present at 39 weeks in the azithromycin group compared to placebo, but no significant difference between the groups at 78 weeks. No differences in change from baseline in myeloperoxidase, calprotectin or absolute neutrophil count were present at either time point. This supports the concept of a transient immunomodulatory effect for chronic azithromycin therapy in children with CF.

Topics: Anti-Bacterial Agents; Azithromycin; Biomarkers; C-Reactive Protein; Child; Cystic Fibrosis; Humans; Leukocyte L1 Antigen Complex; Peroxidase; Pseudomonas

Structural lung disease and neutrophil-dominated airway inflammation is present from 3 months of age in children diagnosed with cystic fibrosis after newborn screening. We hypothesised that azithromycin, given three times weekly to infants with cystic fibrosis from diagnosis until age 36 months, would reduce the extent of structural lung disease as captured on chest CT scans.. A phase three, randomised, double-blind, placebo-controlled trial was done at eight paediatric cystic fibrosis centres in Australia and New Zealand. Infants (aged 3-6 months) diagnosed with cystic fibrosis following newborn screening were eligible. Exclusion criteria included prolonged mechanical ventilation in the first 3 months of life, clinically significant medical disease or comorbidities other than cystic fibrosis, or macrolide hypersensitivity. Participants were randomly assigned (1:1) to receive either azithromycin (10 mg/kg bodyweight orally three times per week) or matched placebo until age 36 months. Randomisation was done with a permuted block strategy and an interactive web-based response system, stratified by study site. Unblinding was done once all participants completed the trial. The two primary outcomes were the proportion of children with radiologically defined bronchiectasis, and the percentage of total lung volume affected by disease. Secondary outcomes included clinical outcomes and exploratory outcomes were inflammatory markers. Analyses were done with the intention-to-treat principle. This study is registered at ClinicalTrials.gov (NCT01270074).. Between June 15, 2012, and July 10, 2017, 281 patients were screened, of whom 130 were enrolled, randomly assigned, and received first study dose. 68 participants received azithromycin and 62 received placebo. At 36 months, 88% (n=50) of the azithromycin group and 94% (n=44) of the placebo group had bronchiectasis (odds ratio 0·49, 95% CI 0·12 to 2·00; p=0·32), and total airways disease did not differ between groups (median difference -0·02%, 95% CI -0·59 to 0·56; p=0·96). Secondary outcome results included fewer days in hospital for pulmonary exacerbations (mean difference -6·3, 95% CI -10·5 to -2·1; p=0·0037) and fewer courses of inhaled or oral antibiotics (incidence rate ratio 0·88, 95% CI 0·81 to 0·97; p=0·0088) for those in the azithromycin group. For the preplanned, exploratory analysis, concentrations of airway inflammation were lower for participants receiving azithromycin, including interleukin-8 (median difference -1·2 pg/mL, 95% CI -1·9 to -0·5; p=0·0012) and neutrophil elastase activity (-0·6 μg/mL, -1·1 to -0·2; p=0·0087) at age 36 months, although no difference was noted between the groups for interleukin-8 or neutrophil elastase activity at 12 months. There was no effect of azithromycin on body-mass index at age 36 months (mean difference 0·4, 95% CI -0·1 to 0·9; p=0·12), nor any evidence of pathogen emergence with the use of azithromycin. There were few adverse outcomes with no differences between the treatment groups.. Azithromycin treatment from diagnosis of cystic fibrosis did not reduce the extent of structural lung disease at 36 months of age; however, it did reduce airway inflammation, morbidity including pulmonary exacerbations in the first year of life and hospitalisations, and improved some clinical outcomes associated with cystic fibrosis lung disease. Therefore we suggest thrice-weekly azithromycin is a strategy that could be considered for the routine early management of paediatric patients with cystic fibrosis.. Cystic Fibrosis Foundation.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiectasis; Child; Child, Preschool; Cystic Fibrosis; Double-Blind Method; Humans; Infant; Infant, Newborn; Inflammation; Interleukin-8; Leukocyte Elastase

Non-cystic fibrosis bronchiectasis (NCFB) brought a heavy healthcare burden worldwide. Macrolide maintenance therapy was proved to be helpful in reducing exacerbation of NCFB. However, the optimal dosing regimens of macrolides have not been determined, and its efficacy in Chinese NCFB population has not been validated. This protocol describes a head-to-head clinical trial designed to compare the efficacy of two dosing regimens of azithromycin in Chinese NCFB population.. This prospective, open-label and randomised controlled trial will be conducted in the First People's Hospital of Jiashan, China. Eligible patients with high-resolution CT defined NCFB will be randomly divided into three groups, which will receive either 250 mg daily azithromycin, or 500 mg three-times-weekly azithromycin or no treatment for 6 months. They will be followed up for another 6 months without treatment. The primary outcome is the mean rate of protocol-defined pulmonary exacerbation at 6 months.. Ethical approval was obtained from the First People's Hospital of Jiashan Ethics Committee. The findings will be disseminated in peer-reviewed publications.. ChiCTR2100052906.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiectasis; Cystic Fibrosis; Fibrosis; Humans; Macrolides; Prospective Studies; Randomized Controlled Trials as Topic

Azithromycin reduces pulmonary exacerbation (PEx) risk in cystic fibrosis (CF), but not all individuals benefit. The goal of this study was to discover blood protein biomarkers predictive of clinical response to azithromycin treatment in children and adolescents with CF.. Novel proteomic technologies were applied to examine 188 serum and plasma protein samples from 40 patients with CF who were randomized to receive azithromycin in the AZ0004 trial. Early changes in blood protein levels from day 0 to day 28 of treatment were examined in relation to changes in FEV. Early changes in the levels of 15 plasma proteins following 28 days of azithromycin significantly correlated with changes in FEV. Early changes in blood protein biomarkers following azithromycin treatment were associated with short-term changes, but not longer term changes, in lung function. Early change in serum calprotectin level was predictive of response to azithromycin in terms of modifying PEx risk.

Topics: Adolescent; Azithromycin; Biomarkers; Child; Cystic Fibrosis; Female; Humans; Male; Predictive Value of Tests; Proteomics; Respiratory Function Tests; Treatment Outcome

New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence.. To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence.. The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF, 6 months to 18 years of age, with early Pa. Azithromycin or placebo was given 3× weekly with standardized TIS.. The primary endpoint was the time to pulmonary exacerbation requiring antibiotics and the secondary endpoint was the time to Pa recurrence, in addition to other clinical and safety outcomes. A total of 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the NHLBI because the trial had reached the prespecified interim boundary for efficacy. The risk of pulmonary exacerbation was reduced by 44% in the azithromycin group as compared with the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.37-0.83; P = 0.004). Weight increased by 1.27 kg in the azithromycin group compared with the placebo group (95% confidence interval, 0.01-2.52; P = 0.046). No significant differences were seen in microbiological or other clinical or safety endpoints.. Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa. Clinical trial registered with clinicaltrials.gov (NCT02054156).

Topics: Administration, Inhalation; Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Cystic Fibrosis; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Infant; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Recurrence; Time Factors; Tobramycin; Treatment Outcome

Concomitant use of oral azithromycin and inhaled tobramycin occurs in approximately half of US cystic fibrosis (CF) patients. Recent data suggest that this combination may be antagonistic.. Test the hypothesis that azithromycin reduces the clinical benefits of tobramycin by analyses of clinical trial data, in vitro modeling of P. aeruginosa antibiotic killing, and regulation of the MexXY efflux pump.. Ongoing administration of azithromycin associates with reduced ability of inhaled tobramycin, as compared with aztreonam, to improve lung function and quality of life in a completed clinical trial. In users of azithromycin FEV. Azithromycin appears capable of reducing the antimicrobial benefits of tobramycin by inducing adaptive bacterial stress responses in P. aeruginosa, suggesting that these medications together may not be optimal chronic therapy for at least some patients.

Topics: Anti-Bacterial Agents; Azithromycin; Aztreonam; Cystic Fibrosis; Drug Administration Routes; Drug Interactions; Drug Monitoring; Female; Humans; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Function Tests; Tobramycin; Treatment Outcome; Young Adult

Pulmonary exacerbations lead to significant morbidity and mortality in patients with cystic fibrosis (CF). National consensus guidelines exist, but few studies report current practice in the treatment and monitoring of pulmonary exacerbations. The goal of this study was to characterize consistency and variability in the inpatient management of CF-related pulmonary exacerbations. We focused on the use of guideline-recommended maintenance therapies, antibiotic selection and treatment regimens, use of systemic corticosteroids, and frequency of lung function testing. We hypothesized that significant variability in these treatment practices exists nationally.. This trial was a retrospective cross-sectional study. It included patients with CF aged ≤18 years hospitalized for pulmonary exacerbations between July 1, 2010, and June 30, 2015, at hospitals within the US Pediatric Health Information System database that are also Cystic Fibrosis Foundation-accredited care centers. One exacerbation per patient was randomly selected over the 5-year study period.. From 38 hospitals, 4827 individual pulmonary exacerbations were examined. Median length of stay was 10.0 days (interquartile range, 6-14.0 days). Significant variation was seen among centers in the use of hypertonic saline (11%-100%), azithromycin (5%-83%), and systemic corticosteroids (3%-61%) and in the frequency of lung function testing. Four different admission antibiotic regimens were used >10% of the time, and the most commonly used admission antibiotic regimen comprised 2 intravenous antibiotics with no additional oral or inhaled antibiotics (29%).. Significant variation exists in the treatment and monitoring of pulmonary exacerbations across Pediatric Health Information System-participating, Cystic Fibrosis Foundation-accredited care centers. Results from this study can inform future research working toward standardized inpatient pulmonary exacerbation management to improve CF care for children and adolescents.

Topics: Adolescent; Adrenal Cortex Hormones; Azithromycin; Child; Child, Preschool; Cross-Sectional Studies; Cystic Fibrosis; Disease Progression; Drug Administration Routes; Female; Guideline Adherence; Hospitalization; Humans; Infant; Length of Stay; Male; Respiratory Function Tests; Retrospective Studies; Saline Solution, Hypertonic

Effectiveness of omega-3 supplementation in cystic fibrosis (CF) remains controversial. This study sought to evaluate clinical status, exercise tolerance, inflammatory parameters, and erythrocyte fatty acid profile after 1 year of oral omega-3 supplementation in CF patients. Fifteen ΔF508-homozygous patients undergoing chronic azithromycin were randomized to receive omega-3 fish oil supplementation at a dose of 60mg/Kg/day or placebo. In comparison with the previous year, in the supplemented group, the number of pulmonary exacerbations decreased at 12 months (1.7 vs. 3.0, p<0.01), as did the duration of antibiotic therapy (26.5 days vs. 60.0 days, p<0.025). Supplementation significantly increased the levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as early as <3 months of administration, with concomitant decreases in arachidonic acid (AA) levels. This pilot study suggests that long-term omega-3 supplementation offers several clinical benefits as to the number of exacerbations and duration of antibiotic therapy in CF patients.

Topics: Adolescent; Adult; Arachidonic Acid; Azithromycin; Child; Child, Preschool; Cystic Fibrosis; Dietary Supplements; Docosahexaenoic Acids; Double-Blind Method; Drug Administration Schedule; Eicosapentaenoic Acid; Fatty Acids; Fatty Acids, Omega-3; Female; Humans; Male; Pilot Projects; Treatment Outcome; Young Adult

Current definitions of pulmonary exacerbation (PE) in cystic fibrosis are based on studies in participants with significant lung disease and may not reflect the spectrum of findings observed in younger patients with early lung disease.. We used data from a recent trial assessing the efficacy of azithromycin in children to study signs and symptoms associated with PEs and related changes in lung function and weight.. While increased cough was present in all PEs, acute weight loss and reduction in oxygen saturation were not observed. Changes in lung function did not differ between subjects who did experience a PE and those who were exacerbation-free.. Cough was the predominant symptom in CF patients with early lung disease experiencing a PE. There was no significant difference in mean 6-month change in lung function or weight among subjects with one or more exacerbations and those without an exacerbation.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Child; Cough; Cystic Fibrosis; Disease Progression; Double-Blind Method; Female; Humans; Lung; Lung Diseases; Male; Middle Aged; Respiratory Function Tests; Respiratory Tract Infections

Recent studies of inhaled tobramycin in subjects with cystic fibrosis (CF) find less clinical improvement than previously observed. Nonhuman data suggest that in some strains of Pseudomonas aeruginosa, azithromycin can antagonize tobramycin.. We tested the hypothesis that concomitant azithromycin use correlates with less improvement in key outcome measures in subjects receiving inhaled tobramycin while not affecting those receiving a comparative, nonaminoglycoside inhaled antibiotic.. We studied a cohort of 263 subjects with CF enrolled in a recent clinical trial comparing inhaled tobramycin with aztreonam lysine. We performed a secondary analysis to examine key clinical and microbiologic outcomes based on concomitant, chronic azithromycin use at enrollment.. The cohort randomized to inhaled tobramycin and reporting azithromycin use showed a significant decrease in the percent predicted FEV1 after one and three courses of inhaled tobramycin when compared with those not reporting azithromycin use (28 d: -0.51 vs. 3.43%, P < 0.01; 140 d: -1.87 vs. 6.07%, P < 0.01). Combined azithromycin and inhaled tobramycin use was also associated with earlier need for additional antibiotics, lesser improvement in disease-related quality of life, and a trend toward less reduction in sputum P. aeruginosa density. Subjects randomized to inhaled aztreonam lysine had significantly greater improvement in these outcome measures, which were unaffected by concomitant azithromycin use. Outcomes in those not using azithromycin who received inhaled tobramycin were not significantly different from subjects receiving aztreonam lysine. Azithromycin also antagonized tobramycin but not aztreonam lysine in 40% of P. aeruginosa clinical isolates tested in vitro.. Oral azithromycin may antagonize the therapeutic benefits of inhaled tobramycin in subjects with CF with P. aeruginosa airway infection.

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Aztreonam; Cystic Fibrosis; Drug Interactions; Female; Forced Expiratory Volume; Humans; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Quality of Life; Tobramycin; Young Adult

In a chronic disease setting such as cystic fibrosis (CF), antibiotics are often prescribed for emergent symptoms and it is unclear whether this affects endpoints in a clinical trial. Pulmonary exacerbations (PEs) are defined episodes of acute worsening and a key clinical efficacy measure in CF. Our hypothesis was that acute antibiotics given for illnesses not meeting the PE definition may alter estimates of treatment effect that do not account for this antibiotic use.. A randomized, placebo-controlled trial of azithromycin (AZ) including 260 participants with CF was utilized for this study. PEs were defined using a priori criteria. Physician initiated antibiotic therapy (PIT) not meeting the PE endpoint was characterized and its impact on treatment effect assessed.. 40% (104/260) of participants were prescribed 188 courses of PIT in the absence of a PE; 19% (25/129) of placebo and 10% (13/131) of AZ participants received ≥2 courses of PIT and never fulfilled the PE definition (9% difference, 95% confidence interval: 1%, 18%, p = 0.04). Accounting for PIT through use of a composite endpoint including time to PE or need for repeated PIT altered treatment effect estimates (a 56% reduction in the event rate comparing AZ to placebo [p < 0.0001] as compared to a 50% reduction not accounting for PIT [p = 0.003]).. PIT is common in CF and may impact treatment effect estimates. Optimization of the PE endpoint to include meaningful events necessitating treatment may improve our ability to conduct efficient trials by reducing the sample size 30-50%, ultimately enabling rapid evaluation of new therapies.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Clinical Protocols; Cystic Fibrosis; Female; Humans; Lung Diseases; Male; Research Design; Sample Size

While the mechanism of action by which azithromycin exerts positive effects inpatients with cystic fibrosis remains unclear, evidence suggests that azithromycin may act as an immunomodulatory agent. We examined changes in systemic inflammatory markers in a doubleblind, randomized, controlled trial of oral azithromycin in patients 6-18 years of age with cystic fibrosis who were uninfected with Pseudomonas aeruginosa.. WBC counts and differential, serum myeloperoxidase (MPO), high-sensitivity C reactive protein (hsCRP), intracellular adhesion molecule 1, IL-6, calprotectin, serum amyloid A (SAA),and granulocyte colony-stimulating factor (G-CSF) were measured at baseline and after 28 and 168 days of treatment in patients receiving either oral azithromycin or placebo.. Inflammatory markers were similar in both groups at baseline. HsCRP, MPO, SAA, calprotectin,and the absolute neutrophil count (ANC) significantly decreased from baseline today 28 in the azithromycin group compared with the placebo group ( P < .05). This treatment effect was sustained at day 168 for ANC, calprotectin, and SAA ( P < .05). Changes in hsCRP, calprotectin,and SAA at day 28 were negatively correlated with changes in FEV 1 (L) and FEV 1(% predicted), as well as both absolute and relative changes in weight ( P < .05). Except for weight (%),the associations remained significant for calprotectin; FEV 1 (L) and weight (%) remained significantly correlated with the 168-day change in hsCRP. The 168-day change in ANC was significantly correlated with changes in lung function, but not in weight; the change in G-CSF was significantly correlated with the change in weight (%) only.. In patients not infected with P aeruginosa , oral azithromycin significantly reduced neutrophil counts and serum inflammatory markers within 28 days of initiating treatment.. ClinicalTrials.gov; No.: NCT00431964; URL: www.clinicaltrials.gov

Topics: Adolescent; Azithromycin; Biomarkers; C-Reactive Protein; Child; Cystic Fibrosis; Double-Blind Method; Female; Granulocyte Colony-Stimulating Factor; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Leukocyte Count; Leukocyte L1 Antigen Complex; Male; Peroxidase; Placebos; Pseudomonas aeruginosa; Respiratory Function Tests; Serum Amyloid A Protein; Treatment Outcome

We previously performed a randomized placebo-controlled trial to examine the effects of azithromycin in children and adolescents 6-18 years of age with cystic fibrosis uninfected with Pseudomononas aeruginosa and demonstrated that while azithromycin did not acutely improve pulmonary function, azithromycin-reduced pulmonary exacerbations, decreased the initiation of new oral antibiotics, and improved weight gain. We now report the results of the open-label, follow-on study to assess durability of response to azithromycin and continued safety and tolerability.. Eligible participants were enrolled in a 24-week open-label study of azithromycin to compare efficacy and safety endpoints during the placebo-controlled trial versus open-label study in two groups: participants initially on azithromycin continued azithromycin (azithromycin-azithromycin) and participants initially on placebo who then received azithromycin (placebo-azithromycin). As in the placebo-controlled trial, the azithromycin dose in the open-label study was 250 mg Monday-Wednesday-Friday for participants weighing 18-35.9 kg and 500 mg Monday-Wednesday-Friday for participants weighing 36 kg or greater.. Of 174 eligible participants, 146 (83.9%) enrolled in the open-label study. No significant improvements in lung function were observed within either group. There were no differences in outcomes in the placebo-azithromycin group during the placebo-controlled versus open-label phase. The azithromycin-azithromycin group had comparable odds of experiencing an exacerbation during the two phases (OR 1.6, CI(95) 0.8, 3.0) and stable weight gain, but new oral antibiotics were initiated more frequently during the open-label study (OR 1.9, CI(95) 1.0, 3.5). In both groups, adverse event rates were comparable during the placebo-controlled and open-label study and treatment-emergent pathogens were rare.. During the open-label study, we observed continued durability of treatment response to azithromycin, as measured by pulmonary exacerbations and continued weight gain, although use of oral antibiotics increased. There were no new safety concerns. Currently available data suggest that azithromycin reduces exacerbations and improves weight gain for 6-12 months among children and adolescents with CF uninfected with P. aeruginosa.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Disease Progression; Female; Follow-Up Studies; Humans; Lung; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Function Tests; Treatment Outcome; Weight Gain

Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulatory properties. We tested the hypothesis that azithromycin would decrease the frequency of exacerbations, increase lung function, and improve health-related quality of life in patients with non-cystic fibrosis bronchiectasis.. We undertook a randomised, double-blind, placebo-controlled trial at three centres in New Zealand. Between Feb 12, 2008, and Oct 15, 2009, we enrolled patients who were 18 years or older, had had at least one pulmonary exacerbation requiring antibiotic treatment in the past year, and had a diagnosis of bronchiectasis defined by high-resolution CT scan. We randomly assigned patients to receive 500 mg azithromycin or placebo three times a week for 6 months in a 1:1 ratio, with a permuted block size of six and sequential assignment stratified by centre. Participants, research assistants, and investigators were masked to treatment allocation. The coprimary endpoints were rate of event-based exacerbations in the 6-month treatment period, change in forced expiratory volume in 1 s (FEV(1)) before bronchodilation, and change in total score on St George's respiratory questionnaire (SGRQ). Analyses were by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000641493.. 71 patients were in the azithromycin group and 70 in the placebo group. The rate of event-based exacerbations was 0·59 per patient in the azithromycin group and 1·57 per patient in the placebo group in the 6-month treatment period (rate ratio 0·38, 95% CI 0·26-0·54; p<0·0001). Prebronchodilator FEV(1) did not change from baseline in the azithromycin group and decreased by 0·04 L in the placebo group, but the difference was not significant (0·04 L, 95% CI -0·03 to 0·12; p=0·251). Additionally, change in SGRQ total score did not differ between the azithromycin (-5·17 units) and placebo groups (-1·92 units; difference -3·25, 95% CI -7·21 to 0·72; p=0·108).. Azithromycin is a new option for prevention of exacerbations in patients with non-cystic fibrosis bronchiectasis with a history of at least one exacerbation in the past year.. Health Research Council of New Zealand and Auckland District Health Board Charitable Trust.

Topics: Adult; Aged; Anti-Bacterial Agents; Azithromycin; Bronchiectasis; Cystic Fibrosis; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Quality of Life; Secondary Prevention; Treatment Outcome; Vital Capacity

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Humans; Phenotype; Placebos; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome

Long-term administration of azithromycin (AZM) in children with cystic fibrosis (CF) has improved outcomes. However, the doses and schedule of administration are not very well studied in children with CF.. A randomized controlled trial was conducted to compare the effect of two doses of azithromycin (5mg/kg/day and 15mg/kg/day) on FEV(1) and pulmonary exacerbations in children with cystic fibrosis. Enrolled children were randomly allocated to receive daily azithromycin (5mg/kg/day or 15mg/kg/day) for 6months. Clinical assessment and FEV(1) measurement were performed monthly.. 56 children (28 in high dose group and 28 in low dose group) were enrolled. 47 (24 and 23 children in low and high dose groups) completed 12months of follow up. There was no difference in clinical scores, FEV(1), pulmonary exacerbation rates between two groups at baseline, 6months and at 12months. Per protocol analysis revealed that pulmonary exacerbation increased after discontinuing AZM and there was significantly more increase after 12months of enrolment in children getting high dose azithromycin. There was no improvement in FEV(1) in either group at the end of treatment period. Children tolerated daily low as well as high dose AZM well for 6months. There was no significant side effect of azithromycin.. In this randomized controlled trial, we did not find differences in the effect of 2 doses (5mg/kg/day or 15mg/kg/day) of AZM on change in percentage predicted FEV(1), clinical scores, Pseudomonas colonization rates, pulmonary exacerbations and need for antibiotics. There was increase in exacerbations after stopping azithromycin in both the groups. Our results also suggest that the decrease in the incidence of LRTI persists only till 6months after discontinuing azithromycin.

Topics: Anti-Bacterial Agents; Azithromycin; Body Weight; Candidiasis; Child; Child, Preschool; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Interleukin-8; Male; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Spirometry; Sputum; Staphylococcal Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus pneumoniae; Treatment Outcome

Azithromycin is recommended as therapy for cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infection, but there has not been sufficient evidence to support the benefit of azithromycin in other patients with CF.. To determine if azithromycin treatment improves lung function and reduces pulmonary exacerbations in pediatric CF patients uninfected with P. aeruginosa.. A multicenter, randomized, double-blind placebo-controlled trial was conducted from February 2007 to July 2009 at 40 CF care centers in the United States and Canada. Of the 324 participants screened, 260 were randomized and received study drug. Eligibility criteria included age of 6 to 18 years, a forced expiratory volume in the first second of expiration (FEV(1)) of at least 50% predicted, and negative respiratory tract cultures for P. aeruginosa for at least 1 year. Randomization was stratified by age of 6 to 12 years vs 13 to 18 years and by CF center.. The active group (n = 131) received 250 mg (weight 18-35.9 kg) or 500 mg (weight > or = 36 kg) of azithromycin 3 days per week (Monday, Wednesday, and Friday) for 168 days. The placebo group (n = 129) received identically packaged placebo tablets on the same schedule.. The primary outcome was change in FEV(1). Exploratory outcomes included additional pulmonary function end points, pulmonary exacerbations, changes in weight and height, new use of antibiotics, and hospitalizations. Changes in microbiology and adverse events were monitored.. The mean (SD) age of participants was 10.7 (3.17) years. The mean (SD) FEV(1) at baseline and 168 days were 2.13 (0.85) L and 2.22 (0.86) L for the azithromycin group and 2.12 (0.85) L and 2.20 (0.88) L for the placebo group. The difference in the change in FEV(1) between the azithromycin and placebo groups was 0.02 L (95% confidence interval [CI], -0.05 to 0.08; P = .61). None of the exploratory pulmonary function end points were statistically significant. Pulmonary exacerbations occurred in 21% of the azithromycin group and 39% of the placebo group. Participants in the azithromycin group had a 50% reduction in exacerbations (95% CI, 31%-79%) and an increase in body weight of 0.58 kg (95% CI, 0.14-1.02) compared with placebo participants. There were no significant differences between groups in height, use of intravenous or inhaled antibiotics, or hospitalizations. Participants in the azithromycin group had no increased risk of adverse events, but had less cough (-23% treatment difference; 95% CI, -33% to -11%) and less productive cough (-11% treatment difference; 95% CI, -19% to -3%) compared with placebo participants.. In children and adolescents with CF uninfected with P. aeruginosa, treatment with azithromycin for 24 weeks did not result in improved pulmonary function.. clinicaltrials.gov Identifier: NCT00431964.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Cough; Cystic Fibrosis; Double-Blind Method; Female; Forced Expiratory Volume; Hospitalization; Humans; Lung; Male; Pseudomonas aeruginosa; Pseudomonas Infections

It was investigated whether azithromycin (AZM) stimulates chloride (Cl-) efflux from cystic fibrosis (CF) and non-CF airway epithelial cells, possibly secondary to up-regulation of the multidrug resistance protein (MDR). CF and non-CF human airway epithelial cell lines (CFBE and 16HBE) were treated with 0.4, 4, and 40 microg/mL AZM for 4 days. Cl- efflux was explored in the presence or absence of specific inhibitors of CFTR and alternative Cl- channels. Six CF patients received AZM (500 mg daily) for 6 months. The percentage of predicted forced vital capacity (FVC%), forced expiratory volume (FEV1%), and the number of acute exacerbations were compared before and after treatment. Nasal biopsies were taken before and after treatment, and mRNA expression of MDR and CFTR was determined by in situ hybridization. A significant dose-dependent increase of Cl- efflux from CFBE cells (but not from 16HBE cells) was observed after AZM treatment. A CFTR inhibitor significantly reduced AZM-stimulated Cl- efflux from CFBE cells. A significant improvement in FEV1%, and fewer exacerbations were observed. AZM treatment did not affect mRNA expression of MDR and CFTR. The stimulation of Cl- efflux could be part of the explanation for the clinical improvement seen among the patients.

Topics: Azithromycin; Case-Control Studies; Cell Line; Chloride Channels; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Epithelial Cells; Female; Humans; Ion Transport; Male; Respiratory Function Tests; Respiratory System; RNA, Messenger; Treatment Outcome; Young Adult

Data on the effects of long-term treatment with azithromycin (AZM) on inflammatory markers in cystic fibrosis patients chronically infected with Pseudomonas aeruginosa are scarce. So far there is no pharmacokinetic and clinical data on once-weekly dosage of AZM in CF patients.. In a randomised double-blind, placebo-controlled trial, patients received AZM or placebo 1 per week for 8 weeks (AZM dosage--20-29 kg: 500 mg, 30-39 kg: 750 mg, 40-49 kg: 1000 mg and > or = 50 kg: 1250 mg) after a course of intravenous antipseudomonal antibiotics. Pulmonary function tests, the serum markers LPS-binding protein (LBP), interleukin-8 (IL-8), CRP, P. aeruginosa alginate in sputum samples and quality of life scores were evaluated.. Thirty-eight patients (21 AZM/17 placebo) (mean age: 23.7 years; mean FEV(1): 62% of predicted) were recruited. After treatment (mean dose of 21.2 mg/kg body weight once a week) pulmonary function declined in both groups compared to baseline (i.e. after cessation of i.v. antibiotics). The AZM group was significantly better for mean changes in serum CRP (AZM: +0.9 mg/l, placebo: +21.6 mg/l, p=0.019), lipopolysaccharide binding protein in serum, LBP (AZM: +0.9 microg/ml, placebo: +7.0 microg/ml, p=0.015), serum interleukin-8 (AZM: -3.1 pg/ml, placebo: +2.9 pg/ml, p=0.001) and alginate in sputum (AZM: +85 microg/ml, placebo: +353 microg/ml, p=0.048). Quality of life was significantly better after AZM and there was no increase in treatment-related adverse events.. Once-weekly azithromycin ameliorated inflammatory reactions and improved quality of life. A decline of pulmonary function after cessation of i.v. antibiotics could not be prevented.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Quality of Life; Treatment Outcome; Young Adult

In this study we examined pharmacokinetics, systemic exposure and sputum penetration of azithromycin (AZM) in CF patients on chronic daily AZM therapy after changing to a once weekly dosing scheme. Eight adult CF patients using AZM 500 mg/day were changed to a once weekly dose of 1000 mg during 3 months. Once per month sputum and blood samples were collected. AZM was quantified in blood plasma and polymorphonuclear neutrophils. The cumulative weekly dose was reduced with a factor of 3.5 (7x500 mg vs. 1x1000 mg weekly). This led to a reduction in area under the curve (AUC+/-S.D.) with a factor of 2.5+/-0.8 in plasma, 2.8+/-0.9 in blood, 2.2+/-1.1 in PMNNs and to a reduction in average sputum concentration with a factor of 3.0 (+/-1.5). At 1000 mg once weekly reduced but still substantial concentrations were achieved in PMNNs and in sputum. Although not significant, a tendency towards less than linear reduction was found. In order to calculate and propose an optimal dosing scheme we need to establish a relation between exposure levels and clinical efficacy.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Neutrophils; Sputum

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.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Drug Resistance, Bacterial; Female; Forced Expiratory Volume; Humans; Linear Models; Male; Phenotype; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory System; Retrospective Studies; Treatment Outcome; Type C Phospholipases; Virulence

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.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Opportunistic Infections; Pneumonia, Bacterial; Vital Capacity

Chronic therapy with the macrolide antibiotic azithromycin (AZM) is widely practiced in the treatment of patients with cystic fibrosis (CF) and chronic lung infection with Pseudomonas aeruginosa. Azithromycin dosage is variable, based on published studies, and not supported by pharmacokinetic data. This study describes the pharmacokinetics of the long-term administration of AZM (500 mg per day) in CF patients. AZM concentrations were quantified in the plasma, blood, isolated polymorphonuclear neutrophils (PMNNs), and sputum of 8 adult CF patients. The AZM distribution t1/2 was 0.1 hours in plasma. The (mean +/- standard deviation) elimination t(1/2) was 102 +/- 20 hours in plasma, 180 +/- 68 hours in blood, and 289 +/- 166 hours in PMNNs. The C(max) of AZM was 0.67 +/- 0.31 mg/L in plasma and 2.01 +/- 0.74 mg/L in blood, of which 1.44 +/- 0.69 mg/L was found in PMNNs. In sputum the concentration of AZM ranged from 12 to 53 mg/L and was still detectable at concentrations in the range 4 to 27 mg/L 10 days after the last dose. On average, the concentration in PMNNs was 2100 times the C(plasma) 24 hours after dosing AZM. These results confirm the accumulation of AZM in PMNNs. The authors conclude that sputum levels are elevated far above plasma and blood concentrations. The long t(1/2) in blood and PMNNs and the slow decrease in sputum levels indicate a less frequent dosing schedule (for instance once weekly) should be studied in future clinical trials of AZM in patients with cystic fibrosis.

Topics: Adult; Anti-Bacterial Agents; Area Under Curve; Azithromycin; Cystic Fibrosis; Drug Administration Schedule; Drug Monitoring; Female; Half-Life; Humans; Male; Neutrophils; Pseudomonas Infections; Reproducibility of Results; Sputum; Treatment Outcome

Macrolides display immunomodulatory effects that may be beneficial in chronic inflammatory pulmonary diseases. The aim of the study was to document whether long term use of azithromycin may be associated with respiratory benefits in young patients with cystic fibrosis.. A multicentre, randomised, double blind, placebo controlled trial was conducted from October 2001 to June 2003. The criteria for enrollment were age older than 6 years and forced expiratory volume in 1 second (FEV1) of 40% or more. The active group received either 250 mg or 500 mg (body weight < or > or =40 kg) of oral azithromycin three times a week for 12 months. The primary end point was change in FEV1.. Eighty two patients of mean (SD) age 11.0 (3.3) years and mean (SD) FEV1 85 (22)% predicted were randomised: 40 in the azithromycin group and 42 in the placebo group. Nineteen patients were infected with Pseudomonas aeruginosa. The relative change in FEV1 at month 12 did not differ significantly between the two groups. The number of pulmonary exacerbations (count ratio 0.50 (95% CI 0.32 to 0.79), p < 0.005), the time elapsed before the first pulmonary exacerbation (hazard ratio 0.37 (95% CI 0.22 to 0.63), p < 0.0001), and the number of additional courses of oral antibiotics were significantly reduced in the azithromycin group regardless of the infectious status (count ratio 0.55 (95% CI 0.36 to 0.85), p < 0.01). No severe adverse events were reported.. Long term use of low dose azithromycin in young patients with cystic fibrosis has a beneficial effect on lung disease expression, even before infection with Pseudomonas aeruginosa.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Long-Term Care; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Treatment Outcome

Fourteen- and 15-member macrolide antibiotics are under investigation as potential therapeutic agents for cystic fibrosis (CF). The nonantibiotic mechanisms of action of these compounds in CF are not understood. We used nasal potential difference (NPD) measurements to test the effect of macrolides on airway epithelial ion (chloride, sodium) transport of CF mice and humans. We tested clarithromycin and azithromycin in mice, and clarithromycin in patients with CF. Baseline and post-treatment NPD was measured in two strains (C57Bl6 and BalbC) of CF transmembrane regulator "knockout" and littermate control mice, and in DeltaF508/DeltaF508 mice. In addition, NPD was measured in 18 human subjects with CF (17 DeltaF-508/DeltaF-508 and 1 DeltaF-508/other) who were undergoing a 12-month, randomized, double-blind crossover study of the effects of clarithromycin on pulmonary outcome in CF. Neither clarithromycin nor azithromycin affected ion transport characteristics of normal or CF nasal epithelium in either mouse or humans. We conclude that the apparent beneficial effects of macrolides on pulmonary outcome in CF are not mediated by their modulation of ion transport.

Topics: Adolescent; Adult; Animals; Azithromycin; Child; Clarithromycin; Cross-Over Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Double-Blind Method; Humans; Ion Transport; Macrolides; Male; Membrane Potentials; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred CFTR; Mice, Knockout; Nasal Mucosa

We recently reported a randomized, placebo-controlled trial of azithromycin in patients with cystic fibrosis (CF) that demonstrated a 6.2% improvement in the 168-d relative change in FEV1 among azithromycin participants compared with placebo participants.. In the current analyses, heterogeneity of treatment response and the association between FEV1 and the risk of pulmonary exacerbations were investigated.. The time to first pulmonary exacerbation, hospitalization rates, and antibiotic use were compared between participants categorized by their relative change in FEV1 % predicted (>or= 5 vs. < 5% improvement) at Day 168. Pulmonary function and exacerbation responses were compared in subgroups of participants characterized by long-term concomitant medications and baseline lung function.. All available data from the 185 randomized participants in the azithromycin trial were included in these analyses.. Compared with placebo participants, a reduced risk of pulmonary exacerbations was observed both among azithromycin participants with >or= 5% and those with < 5% relative improvement in FEV1. Similarly, decreased hospitalization rates and decreased use of oral quinolone and nonquinolone antibiotics were observed in azithromycin participants regardless of improvement in FEV1. Subgroup analyses demonstrated that overall, participants on long-term aerosolized tobramycin and/or rhDNase had worse baseline lung function, but still benefited from azithromycin, as evidenced by a lower risk of exacerbations.. Azithromycin participants experienced benefits in exacerbation parameters regardless of FEV1 response or subgroup. These data have implications for clinical practice and the design of clinical trials.

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Deoxyribonuclease I; Drug Monitoring; Forced Expiratory Volume; Genotype; Heterozygote; Homozygote; Hospitalization; Humans; Pneumonia, Bacterial; Predictive Value of Tests; Proportional Hazards Models; Pseudomonas Infections; Risk Factors; Severity of Illness Index; Tobramycin; Treatment Outcome; United States

Autoantibodies against bactericidal/permeability-increasing protein (BPI-ANCA) were found in patients with cystic fibrosis (CF). It is speculated that they represent a marker of the chronic endobronchial infection and sustained inflammatory response in CF. Our aim was to evaluate whether azithromycin (AZM), through its antiinflammatory effect, could affect the level of BPI-ANCA in CF patients. Eighteen patients with CF aged 5.5-36.3 years (median 15.1) were enrolled in a randomised, double-blind, placebo-controlled trial of AZM (250 mg twice a week to 10 patients) or placebo (8 patients) for 12 weeks. BPI-ANCA levels were recorded pre- and post-treatment and compared to a group of 18 matched healthy controls. Chi-square analysis, Kruskal-Wallis and Mann-Whitney tests were used to compare between the groups. Pre- and post-treatment values were compared using the Wilcoxon Signed-Ranked test. BPI-ANCA was found in 12 CF patients (67%) and four (22%) healthy subjects (P<0.001). The mean BPI-ANCA level was 3.94+/-6.15 U/ml (mean+/-SD) in healthy subjects and 38.11+/-42.34 U/ml in CF patients (P=0.023). The mean BPI-ANCA level was higher in patients with Pseudomonas aeruginosa compared to those without (64+/-35 U/ml and 25+/-41 U/ml respectively, P=0.032). No change in BPI-ANCA levels occurred in the AZM-treated patients [35 (0-127) U/ml (median (range) and 30 (0-120) U/ml, respectively] or in the placebo group [10 (0-66) U/ml and 13 (0-83) U/ml, respectively]. BPI-ANCA levels are significantly higher in patients with CF compared to healthy controls. BPIANCA levels are higher among patients colonised with P. aeruginosa. Twelve weeks of AZM therapy did not lower the BPI-ANCA level in patients with CF.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Autoantibodies; Azithromycin; Blood Proteins; Child; Cystic Fibrosis; Female; Humans; Male; Membrane Proteins; Placebos

Chronic pulmonary infections with Pseudomonas aeruginosa are the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). The macrolide antibiotics exhibit immunomodulatory and antivirulence activity. Clinical trials with azithromycin in CF have demonstrated significant improvements in pulmonary function and decreased hospitalizations. The purpose of this study was to compare the pharmacokinetics (PK) of azithromycin in patients with CF and controls. The study was conducted as an open-label, parallel, two-period crossover study involving 12 healthy volunteers and 12 patients with CF. Period 1 examined the serum PK following a single oral and intravenous dose, while period 2 examined the intracellular PK following multiple-dose oral administration. CF subjects differed significantly from controls based on weight (53.1 versus 71.0 kg; P < 0.01) and body mass index (19.7 versus 23.2; P < 0.01), respectively. Ninety-two percent of CF patients were pancreatic insufficient and were receiving pancreatic enzymes. The rate (time to reach maximum serum drug concentration, 3.0 versus 3.0 h; P = 0.78) and extent of absorption (absolute bioavailability, 34.2 versus 42.8%; P = 0.37) were similar in patients with CF and controls, respectively. Distribution to the tissues (rate of drug transfer from the central to the peripheral compartment, 1.22 versus 0.759 h(-1); P = 0.03) and elimination (rate of elimination from the central compartment, 0.693 versus 0.492 h(-1); P < 0.01) were more rapid in the healthy volunteers than in the CF subjects, respectively. Mononuclear cell concentrations (15.2 +/- 6.0 mg/liter) far exceeded the maximum serum drug concentration ( approximately 50-fold), demonstrating significant intracellular accumulation. These results indicate no alteration in dosage of azithromycin is necessary in patients with CF taking pancreatic enzymes.

Topics: Adult; Azithromycin; Biological Availability; Cross-Over Studies; Cystic Fibrosis; Humans; Pancreas

Following reports on the treatment of diffuse panbronchiolitis (DPB), recent studies demonstrate that long term therapy with azithromycin (AZM) is effective in cystic fibrosis (CF) patients. However, the underlying mechanisms remain uncertain. Some macrolides, including AZM, display inhibition of virulence factors and other antipseudomonal effects at subinhibitory levels in vitro.. Drug doses used for CF and DPB therapy were investigated to determine whether they achieve corresponding sputum drug levels in CF patients in vivo.. In an open, prospective study, 14 CF patients with chronic Pseudomonas aeruginosa airway infection received 250 mg AZM either daily ('high dose') or twice weekly ('low dose') for 12 weeks. Viscoelasticity of sputum was assessed by magnetic microrheology.. AZM accumulated in sputum by two orders of magnitude over a period of four weeks. In the following steady state, median AZM concentrations in sputum were 9.5 microg/mL (0.6 to 79.3 microg/mL, interquartiles 1.4 to 33.4 microg/mL) and 0.5 microg/mL (range less than 0.1 [below detection level] to 5.2 microg/mL, interquartiles 0.2 to 1.4 microg/mL) in the high and low dose groups, respectively. Viscoelasticity improved in all patients but one.. The findings suggest that antipseudomonal activity has to be considered among the potential mechanisms of macrolide therapy. Further, viscoelasticity may be a valuable parameter in future clinical trials.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Dose-Response Relationship, Drug; Female; Humans; Male; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Saliva; Sputum

Bronchiolitis obliterans syndrome remains the leading cause of morbidity and mortality in the pulmonary transplant population. Previous studies show that macrolide antibiotics may be efficacious in the treatment of panbronchiolitis and cystic fibrosis. In the latter, azithromycin decreases the number of respiratory exacerbations, improves FEV1, and improves quality of life. We hypothesized that oral azithromycin therapy may improve lung function in patients with bronchiolitis obliterans syndrome. To test this hypothesis, we conducted an open-label pilot trial using maintenance azithromycin therapy in six lung transplant recipients (250 mg orally three times per week for a mean of 13.7 weeks). In this study, five of these six individuals demonstrated significant improvement in pulmonary function, as assessed by FEV1, as compared with their baseline values at the start of azithromycin therapy. The mean increase in the percentage of predicted FEV1 values in these individuals was 17.1% (p

Topics: Administration, Oral; Adult; Anti-Bacterial Agents; Azithromycin; Bronchiectasis; Bronchiolitis Obliterans; Cystic Fibrosis; Drug Administration Schedule; Follow-Up Studies; Forced Expiratory Volume; Humans; Immunosuppressive Agents; Lung Transplantation; Middle Aged; Pilot Projects; Pulmonary Fibrosis; Quality of Life; Severity of Illness Index; Syndrome; Time Factors; Treatment Outcome

Treatment strategies for cystic fibrosis (CF) lung disease include antibiotics, mucolytics, and anti-inflammatory therapies. Increasing evidence suggests that macrolide antibiotics might be beneficial in patients with CF.. To determine if an association between azithromycin use and pulmonary function exists in patients with CF.. A multicenter, randomized, double-blind, placebo-controlled trial conducted from December 15, 2000, to May 2, 2002, at 23 CF care centers in the United States.. Of the 251 screened participants with a diagnosis of CF, 185 (74%) were randomized. Eligibility criteria included age 6 years or older, infection with Pseudomonas aeruginosa for 1 or more years, and a forced expiratory volume in 1 second (FEV1) of 30% or more. Participants were stratified by FEV1 (> or =60% predicted vs <60% predicted), weight of less than 40 kg vs 40 kg or more, and CF center.. The active group (n = 87) received 250 mg (weight <40 kg) or 500 mg (weight > or =40 kg) of oral azithromycin 3 days a week for 168 days; placebo group (n = 98) received identically packaged tablets.. Change in FEV1 from day 0 to completion of therapy at day 168 and determination of safety. Secondary outcomes included pulmonary exacerbations and weight gain.. The azithromycin group had a mean 0.097-L (SD, 0.26) increase in FEV1 at day 168 compared with 0.003 L (SD, 0.23) in the placebo group (mean difference, 0.094 L; 95% confidence interval [CI], 0.023-0.165; P =.009). Nausea occurred in 17% more participants in the azithromycin group (P =.01), diarrhea in 15% more (P =.009), and wheezing in 13% more (P =.007). Participants in the azithromycin group had less risk of experiencing an exacerbation than participants in the placebo group (hazard ratio, 0.65; 95% CI, 0.44-0.95; P =.03) and weighed at the end of the study an average 0.7 kg more than participants receiving placebo (95% CI, 0.1-1.4 kg; P =.02).. Azithromycin treatment was associated with improvement in clinically relevant end points and should be considered for patients with CF who are 6 years or older and chronically infected with P aeruginosa.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Chronic Disease; Cystic Fibrosis; Double-Blind Method; Female; Forced Expiratory Flow Rates; Hospitalization; Humans; Interleukin-8; Male; Pancreatic Elastase; Proportional Hazards Models; Pseudomonas Infections; Quality of Life; Treatment Outcome

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Biomarkers; Bronchiolitis; C-Reactive Protein; Cystic Fibrosis; Double-Blind Method; Humans; Male; Quality of Life; Treatment Outcome; Vital Capacity

The macrolide antibiotic azithromycin has anti-inflammatory properties potentially beneficial in cystic fibrosis. Since findings of open pilot studies seemed to show clinical benefit, we undertook a formal trial.. 41 children with cystic fibrosis, aged 8-18 years, and with a median forced expiratory volume in 1 s (FEV1) of 61% (range 33-80%) participated in a 15-month randomised double-blind, placebo-controlled crossover trial. They received either azithromycin (bodyweight < or =40 kg: 250 mg daily, >40 kg: 500 mg daily) or placebo for 6 months. After 2 months of washout, the treatments were crossed over. The primary outcome was median relative difference in FEV1 between azithromycin and placebo treatment periods. Sputum cultures, sputum interleukin 8 and neutrophil elastase, exercise testing, quality of life, antibiotic use, and pulmonary exacerbation rates were secondary outcome measures. Side-effects were assessed by pure tone audiometry and liver function tests. Analysis was by intention-to-treat.. Median relative difference in FEV1 between azithromycin and placebo was 5.4% (95% CI 0.8-10.5). 13 of 41 patients improved by more than 13% and five of 41 deteriorated by more than 13% (p=0.059). Forced vital capacity and mid-expiratory flow did not significantly change overall. 17 of 41 patients had 24 fewer oral antibiotic courses when on azithromycin than when taking placebo, and five had six extra courses (p=0.005). Sputum bacterial densities, inflammatory markers, exercise tolerance, and subjective well-being did not change. There were no noticeable side-effects.. A 4-6-month trial of azithromycin is justified in children with cystic fibrosis who do not respond to conventional treatment. The mechanism of action remains unknown.

Topics: Adolescent; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Azithromycin; Child; Cross-Over Studies; Cystic Fibrosis; Double-Blind Method; Exercise Test; Forced Expiratory Volume; Humans; Interleukin-8; Leukocyte Elastase; Pilot Projects; Quality of Life; Sputum

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.. 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.. 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).. 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.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Female; Humans; Long-Term Care; Male; Pneumonia, Bacterial; Prospective Studies; Quality of Life; Sputum; Treatment Outcome

Mycobacterium abscessus is the second most common nontuberculous mycobacterium respiratory pathogen and shows in vitro resistance to nearly all oral antimicrobials. M abscessus treatment success is low in the presence of macrolide resistance.. Does treatment with amikacin liposome inhalation suspension (ALIS) improve culture conversion in patients with M abscessus pulmonary disease who are treatment naive or who have treatment-refractory disease?. In an open-label protocol, patients were given ALIS (590 mg) added to background multidrug therapy for 12 months. The primary outcome was sputum culture conversion defined as three consecutive monthly sputum cultures showing negative results. The secondary end point included development of amikacin resistance.. Of 33 patients (36 isolates) who started ALIS with a mean age of 64 years (range, 14-81 years), 24 patients (73%) were female, 10 patients (30%) had cystic fibrosis, and nine patients (27%) had cavitary disease. Three patients (9%) could not be evaluated for the microbiologic end point because of early withdrawal. All pretreatment isolates were amikacin susceptible and only six isolates (17%) were macrolide susceptible. Eleven patients (33%) were given parenteral antibiotics. Twelve patients (40%) received clofazimine with or without azithromycin as companion therapy. Fifteen patients (50%) with evaluable longitudinal microbiologic data demonstrated culture conversion, and 10 patients (67%) sustained conversion through month 12. Six of the 33 patients (18%) demonstrated mutational amikacin resistance. All were patients using clofazimine or clofazimine plus azithromycin as companion medication(s). Few serious adverse events occurred for ALIS users; however, reduction of dosing to three times weekly was common (52%).. In a cohort of patients primarily with macrolide-resistant M abscessus, one-half of the patients using ALIS showed sputum culture conversion to negative findings. The emergence of mutational amikacin resistance was not uncommon and occurred with the use of clofazimine monotherapy.. ClinicalTrials.gov; No.: NCT03038178; URL: www.. gov.

Topics: Amikacin; Anti-Bacterial Agents; Azithromycin; Clofazimine; Cystic Fibrosis; Drug Resistance, Bacterial; Female; Humans; Leprostatic Agents; Liposomes; Macrolides; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous

Tobramycin inhalation solution (TIS) and chronic azithromycin (AZ) have known clinical benefits for children with CF, likely due to antimicrobial and anti-inflammatory activity. The effects of chronic AZ in combination with TIS on the airway microbiome have not been extensively investigated. Oropharyngeal swab samples were collected in the OPTIMIZE multicenter, randomized, placebo-controlled trial examining the addition of AZ to TIS in 198 children with CF and early P. aeruginosa infection. Bacterial small subunit rRNA gene community profiles were determined. The effects of TIS and AZ were assessed on oropharyngeal microbial diversity and composition to uncover whether effects on the bacterial community may be a mechanism of action related to the observed changes in clinical outcomes.. Substantial changes in bacterial communities (total bacterial load, diversity and relative abundance of specific taxa) were observed by week 3 of TIS treatment for both the AZ and placebo groups. On average, these shifts were due to changes in non-traditional CF taxa that were not sustained at the later study visits (weeks 13 and 26). Bacterial community measures did not differ between the AZ and placebo groups.. This study provides further evidence that the mechanism for AZ's effect on clinical outcomes is not due solely to action on airway microbial composition.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Azithromycin; Bacteria; Child; Cystic Fibrosis; Humans; Microbiota; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Given future challenges in conducting large randomized, placebo controlled trials for future CF therapeutics development, we evaluated the potential for using external historical controls to either enrich or replace traditional concurrent placebo groups in CF trials.. The study included data from sequentially completed, randomized, controlled clinical trials, EPIC and OPTIMIZE respectively, evaluating optimal antibiotic therapy to reduce the risk of pulmonary exacerbation in children with early Pseudomonas aeruginosa infection. The primary treatment effect in OPTIMIZE, the risk of pulmonary exacerbation associated with azithromycin, was re-estimated in alternative designs incorporating varying numbers of participants from the earlier trial (EPIC) as historical controls. Bias and precision of these estimates were characterized. Propensity scores were derived to adjust for baseline differences across study populations, and both Poisson and Cox regression were used to estimate treatment efficacy.. Replacing 86 OPTIMIZE placebo participants with 304 controls from EPIC to mimic a fully historically controlled trial resulted an 8% reduction in risk of pulmonary exacerbations (Hazard ratio (HR):0.92 95% CI 0.61, 1.34) when not adjusting for key baseline differences between study populations. After adjustment, a 37% decrease in risk of exacerbation (HR:0.63, 95% CI 0.50, 0.80) was estimated, comparable to the estimate from the original trial comparing the 86 placebo participants to 77 azithromycin participants on azithromycin (45%, HR:0.55, 95% CI: 0.34, 0.86). Other adjusted approaches provided similar estimates for the efficacy of azithromycin in reducing exacerbation risk: pooling all controls from both studies provided a HR of 0.60 (95% x`CI 0.46, 0.77) and augmenting half the OPTIMIZE placebo participants with EPIC controls gave a HR 0.63 (95% CI 0.48, 0.82).. The potential exists for future CF trials to utilize historical control data. Careful consideration of both the comparability of controls and of optimal methods can reduce the potential for biased estimation of treatment effects.

Topics: Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Humans; Lung; Pseudomonas Infections

Antibiotic allergy is a big problem that may affect the treatment and life quality of patients with cystic fibrosis (CF).. To evaluate predictive factors for confirmed antibiotic hypersensitivity in children with CF.. In this case-controlled study, we examined 15 patients with CF who had been confirmed with antibiotic allergy. Additionally, we included a control group of age- and gender-matched 45 CF patients with no antibiotic allergy. The diagnosis of antibiotic allergy was confirmed in the presence of a compatible history and a positive response in the drug skin test or provocation test. Multiple drug hypersensitivity was classified according to the temporal relationship of antibiotics: (i) distant, (ii) simultaneous, and (iii) sequential. The data were analyzed by conditional logistic regression.. β-lactam allergy was confirmed in eight patients (ceftazidime n = 5, piperacillin-tazobactam n = 3) and non-β-lactam allergy was confirmed in two patients (ciprofloxacin n = 1, azithromycin n = 1). Additionally, multiple drug hypersensitivity in five patients (distant n = 4, sequential n = 1), among whom two patients showed hypersensitivity against ceftazidime/piperacillin-tazobactam+ ciprofloxacin/levofloxacin, two patients showed hypersensitivity against ceftazidime+ ciprofloxacin n = 2, and one patient showed hypersensitivity against piperacillin-tazobactam+ amikacin+ trimethoprim-sulfamethoxazole. All patients (n = 13) with confirmed β-lactam allergy were meropenem tolerant. Multivariate analysis indicated that immediate reactions (, p < 0.001) and allergic evaluation in the first six months after the reaction (p = 0.036) were significant risk factors for the prediction of antibiotic hypersensitivity.. Beta-lactam antibiotic allergy is the most commonly confirmed drug allergy in children with CF. However, unlike normal children, ceftazidime and piperacillin-tazobactam account for the majority.

Topics: Amikacin; Anti-Bacterial Agents; Azithromycin; Case-Control Studies; Ceftazidime; Child; Ciprofloxacin; Cystic Fibrosis; Drug Hypersensitivity; Humans; Levofloxacin; Meropenem; Piperacillin; Retrospective Studies; Tazobactam; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Humans; Pseudomonas aeruginosa

In cystic fibrosis (CF), acute respiratory exacerbations critically enhance pulmonary destruction. Since these mainly occur outside regular appointments, they remain unexplored. We previously elaborated a protocol for home-based upper airway (UAW) sampling obtaining nasal-lavage fluid (NLF), which, in contrast to sputum, does not require immediate processing. The aim of this study was to compare UAW inflammation and pathogen colonization during stable phases and exacerbations in CF patients and healthy controls.. Initially, we obtained NLF by rinsing 10 ml of isotonic saline/nostril during stable phases. During exacerbations, subjects regularly collected NLF at home. CF patients directly submitted one aliquot for microbiological cultures. The remaining samples were immediately frozen until transfer on ice to our clinic, where PCR analyses were performed and interleukin (IL)-1β/IL-6/IL-8, neutrophil elastase (NE), matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1 were assessed.. Non-invasive and partially home-based UAW sampling opens new windows for the assessment of inflammation and pathogen colonization in the unified airway system.

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Interleukin-8; Matrix Metalloproteinase 9; Multiplex Polymerase Chain Reaction; Nasal Lavage

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene is expressed in the heart, but this is not known to cause myocardial dysfunction or abnormalities in the ECG in people with CF. CFTR modulators such as tezacaftor/ivacaftor improve lung function and overall health in people with CF. Minor adverse events have been reported in the early clinical trials, but no consistent changes in the ECGs have been reported. This case highlights an unusual side effect of first degree heart block that occurred after more than 8 months of azithromycin and tezacaftor/ivacaftor in combination. Drug withdrawal and reintroduction confirmed that neither drug alone, but only the combination, caused this change. As tezacaftor/ivacaftor is also present in elexacaftor/tezacaftor/ivacaftor, care may be needed to exclude this delayed interaction with azithromycin.

Topics: Aminophenols; Anti-Bacterial Agents; Azithromycin; Benzodioxoles; Cystic Fibrosis; Drug Combinations; Electrocardiography; Female; Heart Block; Humans; Indoles; Quinolones; Young Adult

Chronic oral azithromycin therapy improves clinical outcomes in people with cystic fibrosis (CF), and is recommended for treatment of CF lung disease. Azithromycin is categorized as pregnancy class B. The data for risk of congenital malformations associated with use of azithromycin during pregnancy ranges from no risk to a small increased risk. As with other chronic medications used to treat CF, potential risk to the infant of use of azithromycin during pregnancy must be weighed against the potential risk to the mother of treatment discontinuation. Women with CF considering pregnancy while on chronic azithromycin should be counseled regarding potential risks and benefits.

Topics: Administration, Oral; Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Female; Humans; Pregnancy; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Risk Factors

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Humans; Retrospective Studies; Tobramycin; Young Adult

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Drug Resistance, Bacterial; Female; Humans; Male; Microbial Sensitivity Tests; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Retrospective Studies

Chronic Azithromycin (AZM) is a common treatment for lung infection. Among adults at risk of cardiac events, AZM use has been associated with cardiovascular harm. We assessed cardiovascular safety of AZM among children with CF, as a secondary analysis of a placebo-controlled, clinical trial, in which study drug was taken thrice-weekly for a planned 18 months. Safety assessments using electrocardiogram (ECG) occurred at study enrollment, and then after 3 weeks and 18 months of participation. Among 221 study participants with a median of 18 months follow-up, increased corrected QT interval (QTc) of ≥30 msec was rare, at 3.4 occurrences per 100 person-years; and incidence of QTc prolongation was no higher in the AZM arm than the placebo arm (1.8 versus 5.4 per 100 person-years). No persons experienced QTc intervals above 500 msec. Long-term chronic AZM use was not associated with increased QT prolongation.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Double-Blind Method; Female; Humans; Long QT Syndrome; Male; Multicenter Studies as Topic; Pseudomonas Infections; Randomized Controlled Trials as Topic; Respiratory Tract Infections

Cystic fibrosis (CF) patients are at risk of acquiring chronic Pseudomonas aeruginosa lung infections. The biofilm mode of growth of P. aeruginosa induces tolerance to antibiotics and the host response; accordingly, treatment failure occurs. Supplemental azithromycin has proven beneficial in CF owing to potential immunomodulatory mechanisms. Clinical studies have demonstrated a reduction in exacerbations in CF patients by avian IgY anti-Pseudomonas immunotherapy. We hypothesise that azithromycin pre-treatment could potentiate the observed anti-Pseudomonas effect of IgY opsonisation in vivo. Evaluation of phagocytic cell capacity was performed using in vitro exposure of azithromycin pre-treated human polymorphonuclear neutrophils to IgY opsonised P. aeruginosa PAO3. A murine lung infection model using nasal planktonic P. aeruginosa inoculation and successive evaluation 24 h post-infection was used to determine lung bacteriology and subsequent pulmonary inflammation. Combined azithromycin treatment and IgY opsonisation significantly increased bacterial killing compared with the two single-treated groups and controls. In vivo, significantly increased bacterial pulmonary elimination was revealed by combining azithromycin and IgY. A reduction in the inflammatory markers mobiliser granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein 2 (MIP-2) and interleukin 1 beta (IL-1β) paralleled this effect. Combination of azithromycin and anti-Pseudomonas IgY potentiated the killing and pulmonary elimination of P. aeruginosa in vitro and in vivo. The augmented effect of combinatory treatment with azithromycin and IgY constitutes a potential clinical application for improving anti-Pseudomonas strategies.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Birds; Colony Count, Microbial; Cystic Fibrosis; Cytokines; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Immunoglobulins; Immunotherapy; Lung; Mice; Mice, Inbred BALB C; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Humans; Pseudomonas Infections; Tobramycin

Azithromycin is commonly prescribed drug for individuals with cystic fibrosis (CF), with demonstrated benefits in reducing lung function decline, exacerbation occurrence and improving nutrition. As azithromycin has antimicrobial activity against components of the uncultured microbiome and increasingly the CF microbiome is implicated in disease pathogenesis - we postulated azithromycin may act through its manipulation. Herein we sought to determine if the CF microbiome changed following azithromycin use and if clinical benefit observed during azithromycin use associated with baseline community structure.. Drawing from a prospectively collected biobank we identified patients with sputum samples prior to, during and after initiating azithromycin and determined the composition of the CF microbial community by sequencing the V3-V4 region of the 16S rRNA gene. We categorized patients as responders if their rate of lung function decline improved after azithromycin initiation. Thirty-eight adults comprised our cohort, nine who had not utilized azithromycin in at least 3 years, and 29 who were completely naïve. We did not observe a major impact in the microbial community structure of CF sputum in the 2 years following azithromycin usage in either alpha or beta-diversity metrics. Seventeen patients (45%) were classified as Responders - demonstrating reduced lung function decline after azithromycin. Responders who were naïve to azithromycin had a modest clustering effect distinguishing them from those who were non-Responders, and had communities enriched with several organisms including Stenotrophomonas, but not Pseudomonas.. Azithromycin treatment did not associate with subsequent large changes in the CF microbiome structure. However, we found that baseline community structure associated with subsequent azithromycin response in CF adults.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Female; Humans; Male; Microbiota; RNA, Ribosomal, 16S; Sputum

Ivacaftor is currently the only CFTR potentiator approved and is increasingly used since the development of CFTR correctors. Ivacaftor is metabolized by CYP3A4 and therefore dose reduction is required when treating patients on ivacaftor with CYP3A4 inhibiting drugs. As this advice is based on studies in healthy volunteers and not in cystic fibrosis (CF) patients, we need to investigate this in both groups to be able to extrapolate these data to CF.. A cohort of CF patients and healthy subjects were exposed to a single dose of ivacaftor in combination with a strong (ritonavir), moderate (clarithromycin) and mild (azithromycin) CYP3A4 inhibitor. Ivacaftor concentrations were measured in all blood samples in order to calculate the pharmacokinetic parameters for ivacaftor.. We found that exposure to ivacaftor was higher in healthy volunteers than in subjects with CF. However this difference was not statistically significant. No differences were observed in the interaction potential of CYP3A4 inhibitors between both study groups. The strong CYP3A4 inhibitor ritonavir, increased exposure to ivacaftor 7 times.. Our data support current recommendations for dose adjustment of ivacaftor in case of co-treatment with CYP3A4 inhibitors in people with CF. However, exposure to ivacaftor was higher in healthy subjects than in CF patients. Further study is needed to investigate the cause and implication of this difference.

Topics: Adult; Aminophenols; Azithromycin; Case-Control Studies; Chloride Channel Agonists; Cystic Fibrosis; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Quinolones; Ritonavir

Treatment failure of Mycobacterium avium complex (MAC) pulmonary disease occurs in about 30% of people with cystic fibrosis (CF) and may be a result of abnormal drug concentrations.. Prospective, cross-over, single-dose PK study of 20 pancreatic insufficient individuals with CF and 10 healthy controls (HC). CF subjects received simultaneous doses of oral azithromycin, ethambutol, and rifampin in the fasting state and with food and pancreatic enzymes, separated by two weeks. HC received fasting doses only. A non-compartmental model was used to estimate PK parameters of drugs and metabolites.. Azithromycin maximum concentration (C. PK profiles of azithromycin and ethambutol were similar between CF and HC, except azithromycin C. ClinicalTrials.gov Identifier: NCT02372383 Prior abstract publication: 1. Martiniano S, Wagner B, Brennan L, Wempe M, Anderson P, Nick J, Sagel S. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. Am J Resp Crit Care Med A4842-A4842, 2017. 2. Martiniano SL, Wagner BD, Brennan L, Wempe MF, Anderson PL, Nick JA, Sagel SD. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. J Cyst Fibros 16: S52-53, 2017.

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Antitubercular Agents; Azithromycin; Cross-Over Studies; Cystic Fibrosis; Ethambutol; Humans; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Prospective Studies; Rifampin

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Disease Progression; Female; Humans; Linear Models; Lung; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Function Tests; Retrospective Studies; Young Adult

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Aztreonam; Child; Cohort Studies; Cystic Fibrosis; Female; Humans; Male; Pseudomonas aeruginosa; Retrospective Studies; Tobramycin; Young Adult

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Humans; Lung; Precision Medicine

Topics: Adaptor Proteins, Signal Transducing; Anti-Bacterial Agents; Autophagy; Azithromycin; Case-Control Studies; Chemokine CCL4; Chloroquine; Cystic Fibrosis; Gene Expression Regulation; Host-Pathogen Interactions; Humans; Immunosuppressive Agents; Interleukin-8; Mycobacterium abscessus; Neutrophils; Phagocytosis; Primary Cell Culture; Reactive Oxygen Species; Signal Transduction; Sirolimus; Wortmannin

Long-term treatment with azithromycin is a therapeutic option in Cystic Fibrosis (CF) patients chronically infected with P. aeruginosa. It was recently shown that azithromycin has direct antimicrobial activity when P. aeruginosa isolates are tested in Roswell Park Memorial Institute medium supplemented with fetal calf serum (RPMI 1640/FCS) by broth microdilution. We now investigated whether (i) azithromycin might also be active against multidrug resistant (MDR) P. aeruginosa isolated from CF patients and (ii) how in vitro sensitivity assays perform in synthetic cystic fibrosis sputum medium (SCFM), a medium that mimics the particular CF airway environment. In 17 (59%) out of 29 MDR P. aeruginosa CF isolates MICs for azithromycin ranged between 0.25 and 8 μg/ml and 12 isolates (41%) showed a MIC ≥512 μg/ml when measured in RPMI/FCS. In contrast, MICs were ≥ 256 μg/ml for all P. aeruginosa MDR isolates when tested in either SCFM or in conventional cation-adjusted Mueller Hinton Broth. High MIC values observed in CF adapted medium SCFM for both PAO1 and MDR P. aeruginosa CF isolates, as opposed to findings in RPMI, argue against routine azithromycin MIC testing of CF isolates.

Topics: Adolescent; Adult; Aged; Azithromycin; Child; Culture Media; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa; Young Adult

Cystic fibrosis (CF) is a serious lung disease, commonly susceptible to Pseudomonas aeruginosa colonization. The dense mucus together with biofilm formation limit drug permeability and prevent the drug from reaching the site of action, causing treatment failure of the bacterial infection. Besides the use of antibiotics, the mucolytic agent N-acetylcysteine (NAC) is recommended to be co-administered in the treatment of CF. Although several formulations have been developed for inhalation therapy to improve the pulmonary condition in CF patients, there is still no comprehensive study on a combined multifunctional dry powder formulation of antibiotics with NAC. In this work, we developed an innovative multifunctional dry powder inhaler (DPI) formulation based on salt formation between NAC and antibiotics and characterized their solid state properties and physical stability. NAC could be spray dried together with three different antibiotics, azithromycin (Azi), tobramycin (Tobra) and ciprofloxacin (Cipro), without the use of organic solvents to form Azi/NAC, Tobra/NAC and Cipro/NAC DPI formulations. Solid-state characterization of these DPI formulations showed that they were amorphous after spray drying. Azi/NAC and Tobra/NAC form co-amorphous salt systems that were physically stable under storage at stress conditions. For particle characterization, the obtained mass median aerodynamic diameters were in a suitable range for inhalation (< 5.0μm). The multifunctional antibiotic/NAC formulations conserved or improved the antibiotic susceptibility and showed promising results regarding the inhibition of P. aeruginosa PA14 biofilm formation.

Topics: Acetylcysteine; Administration, Inhalation; Animals; Anti-Bacterial Agents; Azithromycin; Biofilms; Ciprofloxacin; Cystic Fibrosis; Drug Stability; Drug Storage; Expectorants; Horses; Mucus; Particle Size; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

A major contributor to fatalities in cystic fibrosis (CF) patients stems from infection with opportunistic bacterium Pseudomonas aeruginosa. As a result of the CF patient's vulnerability to bacterial infections, one of the main treatment focuses is antibiotic therapy. However, the highly adaptive nature of P. aeruginosa, in addition to the intrinsic resistance to many antibiotics exhibited by most Gram-negative bacteria, means that multi-drug-resistant (MDR) strains are increasingly prevalent. This makes the eradication of pseudomonal lung infections nearly impossible once the infection becomes chronic. New methods to treat pseudomonal infections are greatly needed in order to eradicate MDR bacteria found within the respiratory tract, and ultimately better the quality of life for CF patients. Herein, we describe a novel approach to combatting pseudomonal infections through the use of bis-2-aminoimidazole adjuvants that can potentiate the activity of a macrolide antibiotic commonly prescribed to CF patients as an anti-inflammatory agent. Our lead bis-2-AI exhibits a 1024-fold reduction in the minimum inhibitory concentration of azithromycin in vitro and displays activity in a Galleria mellonella model of infection.

Topics: Adjuvants, Pharmaceutic; Animals; Anti-Bacterial Agents; Azithromycin; Benzimidazoles; Cystic Fibrosis; Disease Models, Animal; Drug Repositioning; Larva; Microbial Sensitivity Tests; Moths; Pseudomonas aeruginosa; Respiratory Tract Infections

Topics: Administration, Inhalation; Administration, Intravenous; Adult; Anti-Bacterial Agents; Azithromycin; Colistin; Cystic Fibrosis; Disease Progression; Female; Forced Expiratory Volume; Humans; Logistic Models; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Tobramycin; Young Adult

Topics: Administration, Intravenous; Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Disease Progression; Female; Forced Expiratory Volume; Humans; Logistic Models; Male; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Oral azithromycin (AZM) has been shown to reduce airway inflammation and disrupt biofilm formation. However, chronic AZM therapy may result in QT interval (QTc) prolongation.. The goals of this study were twofold: (i) to characterize the risk of QTc prolongation in adult patients with cystic fibrosis (CF) receiving AZM and other potential QTc-prolonging agents, and (ii) to describe and capture the number of potential QTc-prolonging agents patients with CF are prescribed.. A retrospective study was conducted over a 3-year period in an adult CF center. QTc values were recorded from electrocardiograms. Univariate and multivariate analyses were conducted. Standard QTc prolongation definitions (males ≥ 450 msec, females ≥ 470 msec) were used.. A total of 89 adult CF patient's records were reviewed. Sixty-eight patients received chronic AZM therapy. Two male patients had prolonged QTc, but only 1 received chronic AZM therapy. The median QTc interval between patients receiving and not receiving AZM was not significantly different (405 [interquartile range, IQR: 388-425] vs 394 [IQR: 384-413] msec, respectively, p=0.14). Also, the QTc interval for patients taking chronic AZM 500 mg Monday/Wednesday/Friday or 250 mg daily was not significantly different (401 [IQR: 383-419] vs 409 [IQR: 394-427] msec, respectively, p=0.48). When stratified by the number of QTc-prolonging medications (AZM vs no AZM), there was no significant difference in median QTc values between patients receiving zero to ≥ 5 QTc-prolonging medications.. An association between chronic AZM therapy and longer QTc intervals or significant QTc prolongation was not shown.

Topics: Adult; Azithromycin; California; Cystic Fibrosis; Female; Humans; Long QT Syndrome; Male; Retrospective Studies

Overexpression of bacterial efflux pumps is a driver of increasing antibiotic resistance in Gram-negative pathogens. The AcrAB-TolC efflux pump has been implicated in resistance to a number of important antibiotic classes including fluoroquinolones, macrolides, and β-lactams. Antisense technology, such as peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), can be utilized to inhibit expression of efflux pumps and restore susceptibility to antibiotics. Targeting of the AcrAB-TolC components with PPMOs revealed a sequence for

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Bronchi; Carrier Proteins; Cell Culture Techniques; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Epithelial Cells; Escherichia coli Proteins; Female; Gram-Negative Bacteria; Humans; Injections, Intraperitoneal; Lipoproteins; Membrane Transport Proteins; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Morpholinos; Peptides

Infection with Burkholderia cepacia complex (Bcc) results in a heterogeneous clinical course ranging from asymptomatic colonization of the airways to fulminant respiratory failure in patients with cystic fibrosis (CF). Early eradication of Pseudomonas aeruginosa improves clinical outcomes. The efficacy and clinical outcomes following implementation of an eradication protocol for Bcc are less well understood.. We developed and implemented a single center Bcc eradication protocol that included an intensive combination of intravenous, inhaled, and oral antibiotic therapies based on in vitro sensitivities. We conducted a retrospective cohort analysis of clinical outcomes compared to patients with chronic Bcc infection.. Six patients were identified as having a newly acquired Bcc colonization and were placed on the eradication protocol. Sequential sputum samples after completion of the protocol demonstrated sustained clearance of Bcc in all patients. Lung function and nutritional status remained stable in the year following eradication.. Clearance of Bcc from sputum cultures using a standardized protocol was successful at one year and was associated with clinical stability.

Topics: Administration, Inhalation; Administration, Intravenous; Administration, Oral; Adult; Anti-Bacterial Agents; Azithromycin; Burkholderia cepacia complex; Burkholderia Infections; Ceftazidime; Clinical Protocols; Cohort Studies; Consolidation Chemotherapy; Cystic Fibrosis; Drug Therapy, Combination; Female; Humans; Induction Chemotherapy; Male; Middle Aged; Pneumonia, Bacterial; Retrospective Studies; Tobramycin; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult

Azithromycin has been shown to improve lung function and reduce the number of pulmonary exacerbations in patients with cystic fibrosis. Concerns remain, however, regarding the potential emergence of treatment-related respiratory pathogens.. To determine whether chronic azithromycin use (defined as three-times weekly administration) is associated with increased rates of detection of eight specific respiratory pathogens.. We performed a new-user, propensity score-matched retrospective cohort study utilizing data from the Cystic Fibrosis Foundation Patient Registry. Incident azithromycin users were propensity score matched 1:1 with contemporaneous nonusers. Kaplan-Meier curves and Cox proportional hazards regression were used to evaluate the association between chronic azithromycin use and incident respiratory pathogen detection. Analyses were performed separately for each pathogen, limited to patients among whom that pathogen had not been isolated in the 2 years before cohort entry.. After propensity score matching, the mean age of the cohorts was approximately 12 years. Chronic azithromycin users had a significantly lower risk of detection of new methicillin-resistant Staphylococcus aureus, nontuberculous mycobacteria, and Burkholderia cepacia complex compared with nonusers. The risk of acquiring the remaining five pathogens was not significantly different between users and nonusers.. Using an innovative new-user, propensity score-matched study design to minimize indication and selection biases, we found in a predominantly pediatric cohort that chronic azithromycin users had a lower risk of acquiring several cystic fibrosis-related respiratory pathogens. These results may ease concerns that chronic azithromycin exposure increases the risk of acquiring new respiratory pathogens among pediatric patients with cystic fibrosis.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Drug Resistance, Bacterial; Female; Follow-Up Studies; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Propensity Score; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Staphylococcal Infections; Young Adult

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Humans

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Humans; Macrolides; Pseudomonas Infections

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Humans; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Humans; Pseudomonas aeruginosa; Pseudomonas Infections

Pseudomonas aeruginosa (PA) is one of the major opportunistic pathogens which can cause chronic lung infection of cystic fibrosis (CF). The formation of PA biofilm promotes CF development and restricts the antimicrobial efficacies of current antibiotics.. The antimicrobial effects of azithromycin (AZM) and berberine (BER) alone and in combination were evaluated using microdilution method, checkerboard assay, time-kill test, qRT-PCR analysis and absorption method. The treatments of AZM and/or BER were further evaluated in an animal lung infection model via observing survival rate, bacterial burden and histopathology of lung, the levels of pro-/anti-inflammatory cytokines.. AZM-BER were demonstrated to be synergistic against ten clinical PA isolates as well as the standard reference PA ATCC27853, in which PA03 was the most susceptible isolate to AZM-BER with FICI of 0.13 and chosen for subsequent experiments. The synergism of AZM-BER was further confirmed against PA03 in time-kill test and scanning electron microscope (SEM) at their concentrations showing synergism. In PA03, we found that AZM-BER could significantly attenuate productions of a series of virulence factors including alginate, LasA protease, LasB protease, pyoverdin, pyocyanin, chitinase as well as extracellular DNA, and remarkably inhibit the levels of quorum sensing (QS) molecules and the expressions of lasI, lasR, rhlI, rhlR at 1/2×MIC, 1×MIC and 2×MIC. In the infection model, the mice survival were increased markedly, the inflammations of infected lungs were improved greatly along with reduced IL-6, IL-8 and ascended IL-10 at 0.8 mg/kg of AZM combined with 3.2 mg/kg of BER.. BER might be a promising synergist to enhance the antimicrobial activity of AZM in vitro and in vivo.

Topics: Alginates; Animals; Anti-Bacterial Agents; Azithromycin; Bacterial Proteins; Berberine; Biofilms; Chitinases; Cyclophosphamide; Cystic Fibrosis; DNA, Bacterial; Drug Combinations; Drug Synergism; Glucuronic Acid; Hexuronic Acids; Humans; Lung; Metalloendopeptidases; Metalloproteases; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Neutropenia; Oligopeptides; Pseudomonas aeruginosa; Pseudomonas Infections; Pyocyanine; Virulence Factors

Bacterial persisters are a quasidormant subpopulation of cells that are tolerant to antibiotic treatment. The combination of the aminoglycoside tobramycin with fumarate as an antibacterial potentiator utilizes an antipersister strategy that is aimed at reducing recurrent

Topics: Anti-Bacterial Agents; Azithromycin; Biofilms; Cystic Fibrosis; Drug Resistance, Bacterial; Drug Therapy, Combination; Fumarates; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Sputum; Tobramycin

Anti-inflammatory therapy is a logical approach to slowing the inevitable lung function deterioration in cystic fibrosis (CF) patients. This study's aim was to evaluate inflammatory markers and disease progression in paediatric CF patients chronically treated with azithromycin or low-dose prednisolone.. The study included 204 patients with CF and 100 healthy controls; 102 CF patients were treated with basic therapy only (without anti-inflammatory treatment; WAT), and 102 individuals received basic therapy along with azithromycin (n = 59) or low-dose prednisolone (n = 43). The median duration of therapy was 24 months (range 12-82) with azithromycin and 31 months (range 12-180) with prednisolone. A cross-sectional analysis of plasma and sputum biomarkers was performed.. Compared with the healthy controls, the WAT group showed elevated IFN-γ, IL-10 (total), and TGFβ1 concentrations, and decreased TNFα (total) and adrenocorticotropic hormone (ACTH) levels (all p < 0.05). Plasma TNFα (total) concentrations in azithromycin/prednisolone patients were significantly higher than those in WAT patients and similar to those of healthy children. In contrast, IL-10 (total) levels were significantly decreased in azithromycin/prednisolone-treated patients compared with WAT patients. Children from the azithromycin group demonstrated ACTH levels similar to those of healthy controls. Azithromycin-treated patients showed a significantly reduced rate of CF-related liver disease and a significantly increased incidence of glucose metabolism disturbances.. Steady-state anti-inflammatory treatments may have a sustained immunomodulatory action at systemic and local levels in CF patients. Further investigations are needed to assess the effects of supportive azithromycin therapy on the hypothalamic-pituitary-adrenal axis and the incidence of non-pulmonary CF complications.

Topics: Adolescent; Adrenocorticotropic Hormone; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Biomarkers; Child; Cross-Sectional Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Progression; Female; Genotype; Humans; Inflammation; Interferon-gamma; Interleukin-10; Leukocyte Elastase; Male; Prednisolone; Transforming Growth Factor alpha; Transforming Growth Factor beta

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Drug Monitoring; Electrocardiography; Female; Humans; Male; Retrospective Studies

Chronic azithromycin therapy is recommended for CF patients with persistent Pseudomonas aeruginosa colonization. Other macrolide antibiotics have been reported to cause QT prolongation, but cardiac effects of azithromycin have not been studied in pediatric populations. We analyzed changes in QTc interval after starting chronic azithromycin in a pediatric CF population. Adolescent males showed increased QTc intervals after initiation of therapy. Given the possible effects of azithromycin on the QTc interval, particularly in patients predisposed to cardiac events, we suggest that the QTc interval of CF patients should be monitored throughout the course of chronic azithromycin.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Cystic Fibrosis; Electrocardiography; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Long QT Syndrome; Male; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Young Adult

In cystic fibrosis (CF), chronic Pseudomonas aeruginosa infection is associated with increased morbidity, antibiotic treatments and mortality. By linking Australian CF registry data with a national microbiological data set, we examined the association between where treatment was delivered, its intensity and P. aeruginosa antibiotic resistance.. Sputa were collected from paediatric and adult CF patients attending 18 Australian CF centres. P. aeruginosa antibiotic susceptibilities determined by local laboratories were correlated with clinical characteristics, treatment intensity and infection with strains commonly shared among Australian CF patients. Between-centre differences in treatment and antibiotic resistance were also compared.. Large variations in antibiotic usage, maintenance treatment practices and multi-antibiotic resistant P. aeruginosa (MARPA) prevalence exist between Australian CF centres, although the overall proportions of MARPA isolates were similar in paediatric and adult centres (31% vs 35%, P = 0.29). Among paediatric centres, MARPA correlated with intravenous antibiotic usage and the Australian state where treatment was delivered, while azithromycin, reduced lung function and treating state predicted intravenous antibiotic usage. In adult centres, body mass index (BMI) and treating state were associated with MARPA, while intravenous antibiotic use was predicted by gender, BMI, dornase-alpha, azithromycin, lung function and treating state. In adults, P. aeruginosa strains AUST-01 and AUST-02 independently predicted intravenous antibiotic usage.. Increased treatment intensity in paediatric centres and the Australian state where treatment was received are both associated with greater risk of MARPA, but not worse clinical outcomes.

Topics: Administration, Intravenous; Adult; Anti-Bacterial Agents; Australia; Azithromycin; Body Mass Index; Child; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Drug Utilization; Female; Health Facilities; Humans; Male; Microbial Sensitivity Tests; Practice Patterns, Physicians'; Pseudomonas aeruginosa; Pseudomonas Infections; Registries; Respiratory Function Tests; Sex Factors; Sputum

Pulmonary antibiotic delivery is recommended as maintenance therapy for cystic fibrosis (CF) patients who experience chronic infections. However, abnormally thick and sticky mucus present in the respiratory tract of CF patients impairs mucus penetration and limits the efficacy of inhaled antibiotics. To overcome the obstacles of pulmonary antibiotic delivery, we have developed nanocomposite microparticles (nCmP) for the inhalation application of antibiotics in the form of dry powder aerosols.. Azithromycin-loaded and rapamycin-loaded polymeric nanoparticles (NP) were prepared via nanoprecipitation and nCmP were prepared by spray drying and the physicochemical characteristics were evaluated.. The nanoparticles were 200 nm in diameter both before loading into and after redispersion from nCmP. The NP exhibited smooth, spherical morphology and the nCmP were corrugated spheres about 1 μm in diameter. Both drugs were successfully encapsulated into the NP and were released in a sustained manner. The NP were successfully loaded into nCmP with favorable encapsulation efficacy. All materials were stable at manufacturing and storage conditions and nCmP were in an amorphous state after spray drying. nCmP demonstrated desirable aerosol dispersion characteristics, allowing them to deposit into the deep lung regions for effective drug delivery.. The described nCmP have the potential to overcome mucus-limited pulmonary delivery of antibiotics.

Topics: Azithromycin; Cystic Fibrosis; Drug Delivery Systems; Humans; Nanocomposites; Nanoparticles; Particle Size; Respiratory Tract Infections; Sirolimus; Treatment Outcome; X-Ray Diffraction

Recent data suggest a possible relationship between cystic fibrosis (CF) pharmacotherapy, Aspergillus fumigatus colonization (AC) and/or allergic bronchopulmonary aspergillosis (ABPA). The aim of this study was to determine if anti-fungal defence mechanisms are influenced by CF pharmacotherapy, i.e. if (1) neutrophils form CF and non-CF donors differ in their ability to produce chitotriosidase (CHIT-1); (2) if incubation of isolated neutrophils with azithromycin, salbutamol, prednisolone or rhDNase might influence the CHIT-1 activity; and (3) if NETosis and neutrophil killing efficiency is influenced by rhDNase. Neutrophils were isolated from the blood of CF patients (n = 19; mean age 26·8 years or healthy, non-CF donors (n = 20; 38·7 years) and stimulated with phorbol-12-myristate-13-acetate (PMA), azithromycin, salbutamol, prednisolone or rhDNase. CHIT-1 enzyme activity was measured with a fluorescent substrate. NETosis was induced by PMA and neutrophil killing efficiency was assessed by a hyphae recovery assay. Neutrophil CHIT-1 activity was comparable in the presence or absence of PMA stimulation in both CF and non-CF donors. PMA stimulation and preincubation with rhDNase increased CHIT-1 activity in culture supernatants from non-CF and CF donors. However, this increase was significant in non-CF donors but not in CF patients (P < 0·05). RhDNase reduced the number of NETs in PMA-stimulated neutrophils and decreased the killing efficiency of leucocytes in our in-vitro model. Azithromycin, salbutamol or prednisolone had no effect on CHIT-1 activity. Stimulation of isolated leucocytes with PMA and treatment with rhDNase interfered with anti-fungal defence mechanisms. However, the impact of our findings for treatment in CF patients needs to be proved in a clinical cohort.

Topics: Adolescent; Adult; Aged; Albuterol; Aspergillus fumigatus; Azithromycin; Bacteria; Cystic Fibrosis; Deoxyribonucleases; Extracellular Traps; Female; Fungi; Hexosaminidases; Humans; Male; Middle Aged; Neutrophils; Phorbol Esters; Prednisolone; Sputum; Young Adult

Low-dose azithromycin has beneficial effects on severity of the lung disease in cystic fibrosis (CF) patients for a period of 6-12 months after initiation of the treatment. Although its impact in the longer term is uncertain, this treatment is frequently used chronically. The aim of this retrospective study was to investigate the effects of low-dose azithromycin treatment on the progression of CF lung disease in patients treated for more than 12 months.. All of the CF patients followed in our pediatric center and who had been on low-dose azithromycin for more than 12 sequential months were included. The clinical data were collected for one year before and three years after the initiation of the azithromycin treatment. These data comprised lung function analyses, rates of exacerbations and of antibiotic courses, and changes in the airways' bacterial colonization.. A total of 68 patients were included (mean age: 9.95 yrs (3.61)). After 12 months, significant reductions in the numbers of pulmonary exacerbations and antibiotic courses were present. However, this effect was not maintained in the subsequent periods, during which increased rates of both pulmonary exacerbations and antibiotic courses were observed. The lung function decline was not modified during the treatment, and a decreasing time-dependent trend typical of CF was observed for the various parameters. No differences in the airway colonization by pathogens such as Pseudomonas aeruginosa and methicillin-sensitive and/or -resistant Staphyloccocus aureus were observed during the treatment. However, isolated Staphyloccocus aureus strains became resistant to macrolides after 6 months of azithromycin and remained resistant thereafter.. No clinical benefits of low-doses azithromycin were present after one year of treatment in young CF patients. Selection for macrolide-resistant strains of bacteria occurred, which should lead to a reconsideration of the duration of azithromycin treatment in CF.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Disease Progression; Drug Resistance, Bacterial; Female; France; Humans; Lung; Macrolides; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Function Tests; Respiratory System; Retrospective Studies; Staphylococcus aureus

Inflammation is a central contributor to the pathogenesis of cystic fibrosis (CF) pulmonary disease; so limiting the excessive production of inflammatory mediators represents a major therapeutic strategy for slowing the decline in lung function and improving survival. The macrolide antibiotic azithromycin (AZM) has anti-inflammatory properties and immunomodulatory effects that may be beneficial in CF. The aim of this study was to document the long term use of AZM effect on pulmonary function, nutritional status and number of pulmonary exacerbations in patients with CF. Twenty four patients with CF aged 4-23 years followed at Hacettepe University Department of Pediatric Pulmonology between May 2007- December 2014 enrolled in the study from 630 CF patients. They received 10 mg/kg/day of AZM three times a week. Pulmonary function parameters, sputum cultures, body mass index (BMI) Z scores and number of pulmonary exacerbations were analyzed at different time intervals (at the visits at months 6, 9 and 12). Median age of the patients was 14.7 (range 4-23 years) years and median treatment duration was 14 months (range 6-60 months). Initially, median FEV1% was found 68% (range 30%-100%), BMI was found 17.05 (range 13.3-26.5) and oxygen saturation was found 95% (range 84%-99%). At the end of the 6th, 9th and 12th months of the AZM therapy; no significant differences in FEV1% and oxygen saturation parameters were found compared to the initial time, however BMI increased significantly (p=0.03), also the number of pulmonary exacerbations (p < 0.001) and severe exacerbations (p < 0.001) needing intravenous antibiotic treatment were significantly reduced at the 6th and 12th month. At the end of the 12th month of AZM; Methicillin sensitive S. aureus (MSSA) colonization was significantly increased (p=0.005) and increased macrolide resistance was detected (p=0.008). Although, this study could not be designed as a placebo controlled study, the results showed that at least 6 months of AZM treatment led to a significiant reduction in the number of pulmonary exacerbations requiring antibiotics and improvement on nutritional status. Despite increased P. aeruginosa antibiotic resistance and MSSA colonization rates, the lower incidence of acute exacerbations in patients receiving AZM is an important and clinically relevant measure of beneficial effect. Therefore, long term use of AZM may be considered to slow pulmonary deterioration in CF patients with P. aeruginosa colonizatio

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Cystic Fibrosis; Female; Humans; Inflammation; Lung; Male; Nutritional Status; Respiratory Function Tests; Young Adult

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Female; Humans; Male

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Female; Humans; Male

We have previously reported that N-acetylcysteine (NAC), ambroxol and azithromycin (AZM) (partially) correct the chloride efflux dysfunction in cystic fibrosis bronchial epithelial (CFBE) cells with the ΔF508 homozygous mutation in vitro.. In the present paper, we further investigated possible immunomodulatory effects of these drugs on the regulation of the innate immune system by studying the expression of the cytosolic NOD-like receptors NLRC1 and NLRC2, and interleukin (IL)-6 production in CFBE cells.. Under basal conditions, PCR and Western Blot data indicate that the NLRC2 receptor has a reduced expression in CF cells as compared to non-CF (16HBE) cells, but that the NLRC1 expression is the same in both cell lines. AZM significantly upregulated NLRC1 and NLRC2 while NAC upregulated only NLRC2 receptor expression in CF cells. Reduced basal IL-6 production was found in CF cells as compared to non-CF cells. MDP (an NLRC2 agonist), NAC and AZM, but not Tri-DAP (an NLRC1 agonist), increased IL-6 production in CF cells, indicating that in CF cells IL-6 upregulation is independent of NLRC1, but involves the activation of NLRC2.. Overall, the results indicate that NAC and AZM not only can correct the chloride efflux dysfunction but also have a weakly strengthening effect on the innate immune system.

Topics: Acetylcysteine; Azithromycin; Bronchi; Cell Line; Cystic Fibrosis; Epithelial Cells; Humans; Immunity, Innate; Interleukin-6; Nod1 Signaling Adaptor Protein; Nod2 Signaling Adaptor Protein; Up-Regulation

Virus-associated pulmonary exacerbations, often associated with rhinoviruses (RVs), contribute to cystic fibrosis (CF) morbidity. Currently, there are only a few therapeutic options to treat virus-induced CF pulmonary exacerbations. The macrolide antibiotic azithromycin has antiviral properties in human bronchial epithelial cells. We investigated the potential of azithromycin to induce antiviral mechanisms in CF bronchial epithelial cells. Primary bronchial epithelial cells from CF and control children were infected with RV after azithromycin pre-treatment. Viral RNA, interferon (IFN), IFN-stimulated gene and pattern recognition receptor expression were measured by real-time quantitative PCR. Live virus shedding was assessed by assaying the 50% tissue culture infective dose. Pro-inflammatory cytokine and IFN-β production were evaluated by ELISA. Cell death was investigated by flow cytometry. RV replication was increased in CF compared with control cells. Azithromycin reduced RV replication seven-fold in CF cells without inducing cell death. Furthermore, azithromycin increased RV-induced pattern recognition receptor, IFN and IFN-stimulated gene mRNA levels. While stimulating antiviral responses, azithromycin did not prevent virus-induced pro-inflammatory responses. Azithromycin pre-treatment reduces RV replication in CF bronchial epithelial cells, possibly through the amplification of the antiviral response mediated by the IFN pathway. Clinical studies are needed to elucidate the potential of azithromycin in the management and prevention of RV-induced CF pulmonary exacerbations.

Topics: Adolescent; Antiviral Agents; Azithromycin; Bronchi; Case-Control Studies; Cell Survival; Cells, Cultured; Child; Child, Preschool; Cystic Fibrosis; Epithelial Cells; Female; Humans; Infant; Interferons; Male; Picornaviridae Infections; Rhinovirus

Azithromycin reduces exacerbations in cystic fibrosis (CF) patients. Our aim was to investigate its association with nontuberculous mycobacteria isolation and macrolide susceptibility.. From 2006 to 2010, all adult CF subjects at Cochin Hospital (Paris, France) harboring at least one positive NTM isolate were identified (Cases). In a nested case-control study, each Case was individually matched for age and gender with up to 4 CF adults with no NTM isolate (Controls). Clinical data at the time of first NTM isolate (index date) in Cases were compared with those of Controls using multivariate conditional regression analysis.. CF subjects with positive NTM isolates (Cases, n=41) were matched to 155 Controls. Among Cases, 48.7% had isolates from Mycobacterium avium complex and 58.5% from Mycobacterium abscessus complex, and 31 Cases fulfilled the 2007 American Thoracic Society criteria for NTM infection (ATS+ Cases). Cases and ATS+ Cases were more likely to have low body mass index and colonization with Aspergillus fumigatus. Azithromycin was associated with a two-fold reduction in NTM isolates. Only one M. avium complex isolate had acquired macrolide resistance.. These data suggest that azithromycin is a primary prophylaxis for NTM infection in CF adults.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Female; Follow-Up Studies; Humans; Male; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Retrospective Studies; Time Factors; Treatment Outcome; Young Adult

Staphylococcus aureus is one of the most frequent pathogens infecting the respiratory tract of patients with cystic fibrosis (CF). This study was the first to examine S. aureus isolates from CF patients in the Czech Republic. Among 100 S. aureus isolates from 92 of 107 observed patients, we found a high prevalence of resistance to macrolide-lincosamide-streptogramin B (MLS(B)) antibiotics (56%). More than half of the resistant strains (29 of 56) carried a mutation in the MLS(B) target site. The emergence of MLS(B) resistance and mutations conferring resistance to MLS(B) antibiotics was associated with azithromycin treatment (p=0.000000184 and p=0.000681, respectively). Methicillin resistance was only detected in 3% of isolates and the rate of resistance to other antibiotics did not exceed 12%. The prevalence of small-colony variant (SCV) strains was relatively low (9%) and eight of nine isolates with the SCV phenotype were thymidine dependent. The study population of S. aureus was heterogeneous in structure and both the most prevalent community-associated and hospital-acquired clonal lineages were represented. Of the virulence genes, enterotoxin genes seg (n=52), sei (n=49), and sec (n=16) were the most frequently detected among the isolates. The PVL genes (lukS-PV and lukF-PV) have not been revealed in any of the isolates.

Topics: Anti-Bacterial Agents; Azithromycin; Cross Infection; Cystic Fibrosis; Czech Republic; Drug Resistance, Bacterial; Humans; Long-Term Care; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Mutation; Ribosomes; Staphylococcal Infections; Staphylococcus aureus; Thymidine

Azithromycin treatment improves clinical parameters in patients with CF, and alters macrophage activation from a pro-inflammatory (M1) phenotype to a pro-fibrotic, alternatively activated (M2) phenotype. The transcriptional profile of cells from patients receiving azithromycin is unknown.. Gene expression in association with macrophage polarization, inflammation, and tissue remodeling was assessed from sputum samples collected from patients with CF. Transcriptional profiles and clinical characteristics, including azithromycin therapy, were compared.. Expression of NOS2 and TNFα was decreased in subjects receiving azithromycin, whereas expression of M2-associated genes was unaffected. Principal component analysis revealed gene expression profiles consistent with M1- (MMP9, NOS2, and TLR4) or M2-polarization (CCL18, fibronectin, and MR1) in select subject groups. These expression signatures did not significantly correlate with clinical characteristics.. Pro-inflammatory gene expression was low in subjects receiving AZM. Genes were stratified into groupings characteristic of M1- or M2-polarization, suggesting that overall polarization status is distinct among patient groups.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Female; Gene Expression; Gene Expression Profiling; Genome-Wide Association Study; Humans; Inflammation; Inflammation Mediators; Macrophage Activation; Macrophages, Alveolar; Male; Phenotype; Receptors, Immunologic; Respiratory Function Tests

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Female; Humans; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Burkholderia cenocepacia is a virulent pathogen that causes significant morbidity and mortality in patients with cystic fibrosis (CF), survives intracellularly in macrophages, and uniquely causes systemic infections in CF. Autophagy is a physiologic process that involves engulfing non-functional organelles and proteins and delivering them for lysosomal degradation, but also plays a role in eliminating intracellular pathogens, including B. cenocepacia. Autophagy is defective in CF but can be stimulated in murine CF models leading to increased clearance of B. cenocepacia, but little is known about autophagy stimulation in human CF macrophages. IFN-γ activates macrophages and increases antigen presentation while also inducing autophagy in macrophages. We therefore, hypothesized that treatment with IFN-γ would increase autophagy and macrophage activation in patients with CF. Peripheral blood monocyte derived macrophages (MDMs) were obtained from CF and non-CF donors and subsequently infected with B. cenocepacia. Basal serum levels of IFN-γ were similar between CF and non-CF patients, however after B. cenocepacia infection there is deficient IFN-γ production in CF MDMs. IFN-γ treated CF MDMs demonstrate increased co-localization with the autophagy molecule p62, increased autophagosome formation, and increased trafficking to lysosomes compared to untreated CF MDMs. Electron microscopy confirmed IFN-γ promotes double membrane vacuole formation around bacteria in CF MDMs, while only single membrane vacuoles form in untreated CF cells. Bacterial burden is significantly reduced in autophagy stimulated CF MDMs, comparable to non-CF levels. IL-1β production is decreased in CF MDMs after IFN-γ treatment. Together, these results demonstrate that IFN-γ promotes autophagy-mediated clearance of B. cenocepacia in human CF macrophages.

Topics: Adolescent; Adult; Autophagy; Azithromycin; Burkholderia cenocepacia; Burkholderia Infections; Child; Cystic Fibrosis; Female; Humans; Interferon-gamma; Interleukin-1beta; Lysosomes; Macrophages; Male; Microscopy, Confocal; Monocytes; Phagosomes; Young Adult

Pseudomonas aeruginosa is a major pathogen in cystic fibrosis (CF) lung disease. Children with CF are routinely exposed to P. aeruginosa from the natural environment, and by adulthood, 80% of patients are chronically infected. P. aeruginosa in the CF airway exhibits a unique biofilm-like structure, where it grows in small clusters or aggregates of bacteria in association with abundant polymers of neutrophil-derived components F-actin and DNA, among other components. These aggregates differ substantially in size and appearance compared to surface-attached in vitro biofilm models classically utilized for studies but are believed to share properties of surface-attached biofilms, including antibiotic resistance. However, little is known about the formation and function of surface-independent modes of biofilm growth, how they might be eradicated, and quorum sensing communication. To address these issues, we developed a novel in vitro model of P. aeruginosa aggregates incorporating human neutrophil-derived products. Aggregates grown in vitro and those found in CF patients' sputum samples were morphologically similar; viable bacteria were distributed in small pockets throughout the aggregate. The lasA quorum sensing gene was differentially expressed in the presence of neutrophil products. Importantly, aggregates formed in the presence of neutrophils acquired resistance to tobramycin, which was lost when the aggregates were dispersed with DNase, and antagonism of tobramycin and azithromycin was observed. This novel yet simple in vitro system advances our ability to model infection of the CF airway and will be an important tool to study virulence and test alternative eradication strategies against P. aeruginosa.

Topics: Anti-Bacterial Agents; Azithromycin; Biofilms; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Humans; Metalloproteases; Microbial Sensitivity Tests; Neutrophils; Pseudomonas aeruginosa; Pseudomonas Infections; Quorum Sensing; Sputum; Tobramycin; Virulence Factors

Certain antibiotics may cause unwanted side effects due to the similarity of the mitochondrial translation system to the prokaryotic one. Children with cystic fibrosis (CF) are vulnerable to recurrent respiratory tract infections and azithromycin, a translation targeted antibiotic, is often used chronically to treat CF patients. No major clinical side effects were found with chronic treatment. However, mitochondrial function was not previously assessed. We evaluated oxidative phosphorylation (OXPHOS) in lymphocytes from children with CF receiving chronic azithromycin treatment using an improved ATP production assay.. Enzymatic activities of respiratory chain complexes II-IV and ATP production were measured in lymphocytes.. Relative to controls and to CF patients without azithromycin treatment, no significant difference in mitochondrial respiratory chain complexes II-IV was detected, and ATP production with pyruvate, glutamate and succinate, did not disclose any differences between the groups.. We suggest that chronic treatment with azithromycin does not significantly affect OXPHOS function.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Electron Transport Complex I; Electron Transport Complex II; Female; Humans; Lymphocytes; Male; Mitochondria; Oxidative Phosphorylation

Persons with cystic fibrosis (CF) are at high risk of nontuberculous mycobacterial (NTM) infection, with treatment requiring prolonged multidrug regimens that include macrolides. Although macrolides, specifically azithromycin, are used in the management of patients with CF with chronic Pseudomonas, macrolide-resistant NTM infections are of growing concern.. To evaluate the relationship between chronic macrolide use and NTM infection among patients with CF included in the 2011 CF Patient Registry (CFPR).. We performed a nested case-control study: incident NTM cases were persons aged more than 5 years with at least one positive culture for NTM in 2011. Controls were persons with negative cultures in 2010 and 2011.. The 2011 CFPR included 27,112 patients; 5,403 (20%) were cultured for mycobacteria in 2010-2011 and met all inclusion criteria. Of these, 191 (4%) were NTM-positive in 2011 only (cases); 5,212 (96%) were NTM-negative in 2010 and 2011 (control subjects). Among the cases, 122 (64%) were culture-positive for Mycobacterium avium complex (MAC) and 69 (36%) for M. abscessus. Azithromycin use in 2010 was less frequently reported among MAC cases (57%; odds ratio = 0.7, P < 0.05) and M. abscessus cases (51%; odds ratio = 0.5, P < 0.01) than in control subjects (66%). Among adolescents and adults, patients with the greatest number of years on chronic macrolides were the least likely to develop incident NTM in 2011 (P < 0.01).. Patients with incident NTM infections from either MAC or M. abscessus were less likely to have had chronic azithromycin treatment in the past year. However, because macrolide monotherapy may lead to macrolide resistance, routine screening for NTM should be considered for persons with CF.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Case-Control Studies; Child; Child, Preschool; Comorbidity; Cystic Fibrosis; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Female; Humans; Macrolides; Male; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Registries; Young Adult

Azithromycin is widely used as an immunomodulatory agent in the treatment of cystic fibrosis with previous literature documenting improvements in lung function and a reduction in infective exacerbations. The maximal study period in adults has been six months.. 81 adult patients taking continuous azithromycin were retrospectively identified. Percentage predicted FEV(1) and courses of intravenous antibiotics were examined at yearly intervals two years prior to and two years after azithromycin initiation.. FEV(1) deteriorated in the two years before starting azithromycin by a mean of 2.02% per year. In the year following initiation, FEV(1) increased by 1.15% (P=0.01). However, a mean 2.58% reduction was observed in year two. There was no statistically significant effect on courses of intravenous antibiotics.. Azithromycin resulted in an improved FEV(1) at year one. This effect was not sustained beyond the first year of treatment.

Topics: Adult; Ambulatory Care Facilities; Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Lung; Maintenance Chemotherapy; Male; Retrospective Studies; United Kingdom; Young Adult

Cystic fibrosis (CF) patients are at particularly high risk of developing lung disease caused by Mycobacterium abscessus complex (MABSC). Over the last 10 years, changes in CF treatment, with increasing use of inhaled therapies and low-dose azithromycin, have been accompanied by an increase in the prevalence of MABSC infections in CF patients. There is therefore some concern about the role of new CF treatments in the emergence of MABSC infections. We addressed this issue by means of a case-control study including 30 MABSC-positive cases and 60 nontuberculous mycobacteria-negative CF controls matched for age, sex and centre. We also compared practices at the CF centres with the highest prevalence of MABSC with those at the other centres. No positive association was found between MABSC lung disease and the use of inhaled therapies or low-dose azithromycin in the 4 years preceding MABSC isolation. These treatments were not significantly more frequently used at the CF centres with the highest MABSC prevalence rates. In conclusion, there is no evidence for a link between M. abscessus complex lung disease and inhaled therapies or low-dose azithromycin in patients with CF.

Topics: Administration, Inhalation; Adolescent; Anti-Bacterial Agents; Azithromycin; Case-Control Studies; Cystic Fibrosis; Female; France; Humans; Lung Diseases; Male; Mycobacterium Infections; Nontuberculous Mycobacteria; Prevalence; Registries; Risk Factors; Young Adult

Macrolide antibiotics, like erythromycin, clarithromycin, and azithromycin, possess anti-inflammatory properties. These properties are considered fundamental to the efficacy of these three macrolides in the treatment of chronic inflammatory diseases like diffuse panbronchiolitis and cystic fibrosis. However, long-term treatment with macrolide antibiotics presents a considerable risk for promotion of bacterial resistance. We have examined antibacterial and anti-inflammatory effects of a novel macrolide class: N'-substituted 2'-O,3'-N-carbonimidoyl bridged erythromycin-derived 14- and 15-membered macrolides. A small focused library was prepared, and compounds without antimicrobial activity, which inhibited IL-6 production, were selected. Data analysis led to a statistical model that could be used for the design of novel anti-inflammatory macrolides. The most promising compound from this library retained the anti-inflammatory activity observed with azithromycin in lipopolysaccharide-induced pulmonary neutrophilia in vivo. Importantly, this study strongly suggests that antimicrobial and anti-inflammatory activities of macrolides are independent and can be separated, which raises development plausibility of novel anti-inflammatory therapeutics.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Azithromycin; Bronchiolitis; Bronchoalveolar Lavage Fluid; Cell Line; Clarithromycin; Cystic Fibrosis; Drug Interactions; Drug Resistance, Bacterial; Erythromycin; Haemophilus Infections; Haemophilus influenzae; Humans; Interleukin-6; Lipopolysaccharides; Lung; Macrolides; Male; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Moraxella catarrhalis; Neutrophils; Rats; Rats, Sprague-Dawley; Streptococcus

Cystic fibrosis is a hereditary disease caused by a mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene that encodes a chloride (Cl(-)) channel. Cystic fibrosis pulmonary pathophysiology is characterised by chronic inflammation and bacterial infections. Azithromycin, a macrolide antibiotic, has shown promising anti-inflammatory properties in some inflammatory pulmonary diseases. Moreover, all clinical studies have presented an improvement of the respiratory condition of cystic fibrosis patients, but the molecular and cellular mechanisms remain unknown. The aim of this study was to investigate, in bronchial epithelial cells, the effects of azithromycin on inflammatory pathways involved in cystic fibrosis. We have analysed the effects of azithromycin on cystic fibrosis and non-cystic fibrosis bronchial epithelial cell lines but also in non-immortalized non-cystic fibrosis human glandular cells. To create an inflammatory context, cells were treated with Tumor Necrosis Factor (TNF)-α or Interleukin (IL)1-β. Activation of the NF-κB pathway was investigated by luciferase assay, western blotting, and by Förster Resonance Energy Transfer imaging, allowing the detection of the interaction between the transcription factor and its inhibitor in live cells. In all conditions tested, azithromycin did not have an anti-inflammatory effect on the cystic fibrosis human bronchial epithelial cells and on CFTR-inhibited primary human bronchial glandular cells. More, our data showed no effect of azithromycin on IL-1β- or TNF-α-induced IL-8 secretion and NF-κB pathway activation. Taken together, these data show that azithromycin is unable to decrease in vitro inflammation in cystic fibrosis cells from airways.

Topics: Azithromycin; Bronchi; Cell Line; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Inflammation; Interleukin-1beta; Interleukin-8; NF-kappa B; Signal Transduction; Tumor Necrosis Factor-alpha

Clonal isolates identified as various nonfermentative Gram-negative bacilli over a 5-year period from sputum cultures of a 30-year-old cystic fibrosis patient were successfully reidentified as Pandoraea sputorum by combining 16S rRNA sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Decreased lung function improved after 1 year of azithromycin and inhaled 7%-hypertonic saline treatment.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Burkholderiaceae; Cluster Analysis; Cystic Fibrosis; DNA Fingerprinting; DNA, Bacterial; DNA, Ribosomal; Electrophoresis, Gel, Pulsed-Field; Female; Gram-Negative Bacterial Infections; Humans; Lung; Mass Spectrometry; Molecular Sequence Data; Phylogeny; Respiratory Function Tests; RNA, Ribosomal, 16S; Sequence Analysis, DNA; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sputum

The emergence of antibiotic-resistant Pseudomonas aeruginosa is an important concern in the treatment of long-term airway infections in cystic fibrosis patients. In this study, we report the occurrence of azithromycin resistance among clinical P. aeruginosa DK2 isolates. We demonstrate that resistance is associated with specific mutations (A2058G, A2059G, and C2611T in Escherichia coli numbering) in domain V of 23S rRNA and that introduction of A2058G and C2611T into strain PAO1 results in azithromycin resistance.

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Point Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; RNA, Bacterial; RNA, Ribosomal, 23S

to determine the mechanism(s) of macrolide resistance in Haemophilus influenzae isolated from cystic fibrosis (CF) patients participating in a randomized placebo-controlled trial of azithromycin.. macrolide susceptibility, mutations and carriage of the macrolide resistance genes erm(A), erm(B), erm(C), erm(F) and mef(A) were determined using PCR assays and sequencing or hybridization of the PCR products. H. influenzae isolates were used as donors in conjugation studies with H. influenzae and Enterococcus faecalis recipients. Transconjugant susceptibility and the macrolide resistance genes carried were determined.. of the 106 H. influenzae isolates, 27 were resistant and 78 intermediate resistant to azithromycin and/or erythromycin. All isolates carried one or more macrolide resistance gene(s), with the mef(A), erm(B) and erm(F) genes found in 74%, 31% and 29% of the isolates, respectively. None of the selected isolates had L4 or L22 mutations. Twenty-five donors, with various macrolide MICs, transferred macrolide resistance genes to H. influenzae Rd (3.5 × 10(-7)-1 × 10(-10)) and/or E. faecalis (1 × 10(-7)-1 × 10(-8)) recipients. The H. influenzae transconjugants were phenotypically resistant or intermediate to both macrolides while E. faecalis transconjugants were erythromycin resistant.. this is the first identification of erm(A), erm(C) and erm(F) genes in H. influenzae or bacteria from CF patients and the first characterization of macrolide gene transfer from H. influenzae donors. The high level of H. influenzae macrolide gene carriage suggests that the use of azithromycin in the CF population may ultimately reduce the effectiveness of continued or repeated macrolide therapy.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Conjugation, Genetic; Cystic Fibrosis; DNA, Bacterial; Drug Resistance, Bacterial; Gene Transfer, Horizontal; Genes, Bacterial; Haemophilus Infections; Haemophilus influenzae; Humans; Macrolides; Microbial Sensitivity Tests; Nucleic Acid Hybridization; Polymerase Chain Reaction; Prevalence; Randomized Controlled Trials as Topic; Sequence Analysis, DNA

We report a case of colchicine-induced rhabdomyolysis in a heart/lung-transplanted man treated with cyclosporin. A treatment was to resolve an acute gouty arthritis and was started with 3 mg of colchicine the first day, then 2 mg the second and the third day, and finally 1 mg/d during 6 days. Eight days later, the patient developed multiple organ failure and rhabdomyolysis. The concentration of colchicine analyzed was greater than the standard 153 hours after his last intake. Pharmacokinetic interactions are responsible of this toxicity. Cyclosporin, pravastatin, and azithromycin are known to inhibit P-glycoprotein, which will enhance the intracellular colchicine level by acting in its bioavailability and moderating hepatic and renal excretion. Moreover, long-term treatment by cyclosporin generates chronic renal failure that will, in the same time, decrease colchicine elimination. Even short-term administration of therapeutic colchicine dose may cause colchicine-related toxicity, especially in the setting of a renal failure and/or polymedicinal treatment.

Topics: Adult; Anti-Bacterial Agents; Anticholesteremic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azithromycin; Colchicine; Cyclosporine; Cystic Fibrosis; Drug Interactions; Gout; Gout Suppressants; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Multiple Organ Failure; Pravastatin; Rhabdomyolysis

Azithromycin (AZM) has shown promising anti-inflammatory properties in chronic obstructive pulmonary diseases, and clinical studies have presented an improvement in the respiratory condition of cystic fibrosis (CF) patients. The aim of this study was to investigate, in human airway cells, the mechanism by which AZM has beneficial effects in CF. We demonstrated that AZM did not have any anti-inflammatory effect on CF airway cells but restored Cl(-) efflux.

Topics: Anti-Bacterial Agents; Azithromycin; Biological Transport; Cell Line; Cells, Cultured; Chlorides; Cystic Fibrosis; Epithelial Cells; Humans; Respiratory System

This study examined the relationship of medication adherence to frequency of pulmonary exacerbation and rate of decline in FEV(1)% predicted (FEV(1)).. 95 CF patients aged 6 years or older and prescribed a pulmonary medication, were enrolled in a longitudinal retrospective review of medication adherence and health outcomes (the occurrence and frequency of intravenous (IV) antibiotic treatments and FEV(1)) over 12-months. Pharmacy refill records were used to calculate a medication possession ratio (MPR).. Composite MPR predicted the occurrence of at least one pulmonary exacerbation requiring a course of IV antibiotics (IRR=2.34, p=0.05), but not the frequency of exacerbations, after controlling for gender, baseline FEV(1,) and regimen complexity. Composite MPR predicted baseline FEV(1) (estimate=29.81, p=.007), but not decline in FEV(1).. These results demonstrate a significant relation between medication adherence and IV antibiotics in CF patients, highlighting the importance of addressing adherence during clinic visits to improve health outcomes.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Deoxyribonuclease I; Drug Prescriptions; Female; Forced Expiratory Volume; Humans; Infusions, Intravenous; Longitudinal Studies; Male; Medication Adherence; Outcome Assessment, Health Care; Pharmacy; Retrospective Studies; Tobramycin; Young Adult

Azithromycin is a potent macrolide antibiotic with poorly understood antiinflammatory properties. Long-term use of azithromycin in patients with chronic inflammatory lung diseases, such as cystic fibrosis (CF), results in improved outcomes. Paradoxically, a recent study reported that azithromycin use in patients with CF is associated with increased infection with nontuberculous mycobacteria (NTM). Here, we confirm that long-term azithromycin use by adults with CF is associated with the development of infection with NTM, particularly the multi-drug-resistant species Mycobacterium abscessus, and identify an underlying mechanism. We found that in primary human macrophages, concentrations of azithromycin achieved during therapeutic dosing blocked autophagosome clearance by preventing lysosomal acidification, thereby impairing autophagic and phagosomal degradation. As a consequence, azithromycin treatment inhibited intracellular killing of mycobacteria within macrophages and resulted in chronic infection with NTM in mice. Our findings emphasize the essential role for autophagy in the host response to infection with NTM, reveal why chronic use of azithromycin may predispose to mycobacterial disease, and highlight the dangers of inadvertent pharmacological blockade of autophagy in patients at risk of infection with drug-resistant pathogens.

Topics: Adult; Animals; Anti-Bacterial Agents; Autophagy; Azithromycin; Chlorocebus aethiops; COS Cells; Cystic Fibrosis; Drug Resistance, Bacterial; Enzyme Inhibitors; HeLa Cells; Humans; Lysosomes; Macrolides; Macrophages; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Mycobacterium; Mycobacterium Infections; Phagosomes; Recombinant Fusion Proteins; Sirolimus

Organisms belonging to the Streptococcus milleri group (SMG) are known for their role in pyogenic infections but have recently been implicated as etiological agents of pulmonary exacerbation in adult patients with cystic fibrosis (CF). The prolonged exposure of CF patients to antibiotics prompted us to investigate the susceptibility profiles of 118 SMG isolates from the airways of CF patients to 12 antibiotics compared to 43 SMG isolates from patients with invasive infections. We found that approximately 60% of all isolates failed to grow using the standard medium for disc diffusion, Mueller-Hinton blood agar (MHBA), so we explored the usefulness of brain heart infusion (BHI) agar for susceptibility testing. Zone-of-inhibition comparisons between BHI and MHBA showed strong correlations for six antibiotics, and interpretations were similar for both medium types. For ceftriaxone and cefepime, both groups of isolates were highly susceptible. Tetracycline resistance levels were comparable between the two groups (22% in CF isolates and 17.4% in invasive isolates). However, more than half of the CF isolates were not susceptible to azithromycin, erythromycin, and clindamycin, compared to 11%, 13%, and 6.5% of invasive isolates, respectively. There were 5-fold and 8-fold increased risks of azithromycin and clindamycin resistance, respectively, for the isolates from the airways of CF patients relative to the invasive isolates. Macrolide resistance was strongly linked to chronic azithromycin therapy in CF patients. This study shows that BHI agar is a suitable alternative for antimicrobial susceptibility testing for the SMG and that SMG isolates from the airways of CF patients are more resistant to macrolides and clindamycin than strains isolated from patients with invasive infections.

Topics: Anti-Bacterial Agents; Azithromycin; Clindamycin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Erythromycin; Humans; Macrolides; Streptococcus milleri Group; Tetracycline

Tight junctions (TJs) play a key role in maintaining bronchial epithelial integrity, including apical-basolateral polarity and paracellular trafficking. Patients with chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) often suffer from chronic infections by the opportunistic Gram-negative bacterium Pseudomonas aeruginosa, which produces multiple virulence factors, including rhamnolipids. The macrolide antibiotic azithromycin (azm) has been shown to improve lung function in patients with CF without reducing the bacterial count within the lung. However, the mechanism of this effect is still debated. It has previously been shown that azm increased transepithelial electrical resistance (TER) in a bronchial epithelial cell line. In this study we used an air-liquid interface model of human airway epithelia and measured TER, changes in TJ expression and architecture after exposure to live P. aeruginosa PAO1, and PAO1-Deltarhl which is a PAO1 mutant lacking rhlA and rhlB, which encode key enzymes for rhamnolipid production. In addition, the cells were challenged with bacterial culture medium conditioned by these strains, purified rhamnolipids, or synthetic 3O-C(12)-HSL. Virulence factors secreted by P. aeruginosa reduced TER and caused TJ rearrangement in the bronchial epithelium, exposing the epithelium to further bacterial infiltration. Pretreatment of the bronchial epithelium with azm attenuated this effect and facilitated epithelial recovery. These data suggest that azm protects the bronchial epithelium during P. aeruginosa infection independent of antimicrobial activity, and could explain in part the beneficial results seen in clinical trials of patients with CF.

Topics: Actins; Anti-Bacterial Agents; Azithromycin; Bronchi; Cell Line; Cystic Fibrosis; Cytoskeleton; Epithelial Cells; Humans; Lipids; Microscopy, Confocal; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Tight Junctions; Virulence Factors

Pulmonary exacerbations are a major cause of morbidity in cystic fibrosis (CF) and likely contribute to lung function decline. Exacerbations are often associated with characteristic airway bacteria [CF related bacteria (CFRB)]. However, some patients do not have CFRB detected by culture during exacerbations.. We sought to determine the proportion of airway cultures negative for CFRB during pulmonary exacerbations, and to characterize patients who were CFRB-negative versus CFRB-positive.. We performed a retrospective study of patients with CF admitted for a pulmonary exacerbation. Patients were classified as CFRB-positive or CFRB-negative based on admission airway cultures. Demographics, clinical presentation, lung function, history of chronic Pseudomonas aeruginosa infection and improvement in lung function with treatment were compared between groups.. There were 672 admissions for exacerbation involving 211 patients over 5 years. Seventeen percent were classified as CFRB-negative. Forty-one percent of bronchoalveolar lavage (BAL), 32% of throat and 10% of sputum samples were CFRB-negative. Among patients capable of expectorating sputum, the CFRB-negative group was younger, less likely to have chronic P. aeruginosa, had higher lung function and body mass index (BMI), and had a lower systemic inflammatory response on admission compared to those with CFRB-positive cultures. The two groups had similar numbers of patients with three or more signs and symptoms of a pulmonary exacerbation (88% vs. 92%). Both groups returned to baseline lung function following treatment.. A significant number of patients with CF and pulmonary exacerbation did not have typical CFRB detected by culture. Patients without CFRB still had characteristic signs and symptoms of pulmonary exacerbation and responded to treatment. Understanding the causes of illness in these patients may improve the diagnosis and treatment of pulmonary exacerbations in CF.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Bronchoalveolar Lavage Fluid; Child; Cystic Fibrosis; Disease Progression; Female; Humans; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Sputum; Tobramycin; Young Adult

Chronic airway inflammation characterizes patients with cystic fibrosis (CF). The role of alternative macrophage activation in this disease course is unknown.. We evaluated markers of alternative and classical macrophage activation in the lungs of patients with CF and evaluated these characteristics in the context of Pseudomonas aeruginosa (PA) infection, immunomodulatory drug therapy and pulmonary function.. Bronchoalveolar lavage or spontaneously expectorated sputum samples were collected from 48 CF patients. Clinical data were related to macrophage surface expression of mannose receptor (MR) (up-regulated in alternatively activated macrophages) and TLR4 (up-regulated in classically activated macrophages). Also, the activity of the alternatively activated macrophage effector molecule arginase was compared among patient groups, and pro- and anti-inflammatory cytokines produced by alternatively and classically activated macrophages were measured.. There were significant differences between PA-infected and -uninfected patients in several clinical measurements. PA-infected patients exhibited increased use of azithromycin, up-regulation of MR on CD11b+ cells and increased arginase activity in their lung samples, and had a strong inverse relationship between MR and arginase activity to FEV(1). Upon further analysis, PA-infected patients who were treated with azithromycin had the highest arginase activity and the highest number of macrophages that were MR+TLR4-, and both of these markers were inversely related to the FEV(1).. Our findings suggest an increase in both MR and arginase expression as pulmonary function declines in PA-infected patients with CF. These markers of an alternatively activated macrophage phenotype give cause for future study to define the function of macrophage activation states in the CF lung.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Arginase; Azithromycin; Biomarkers; Cell Count; Child; Child, Preschool; Cystic Fibrosis; Cytokines; Female; Forced Expiratory Volume; Humans; Infant; Lectins, C-Type; Macrophage Activation; Macrophages; Male; Mannose Receptor; Mannose-Binding Lectins; Middle Aged; Phenotype; Pseudomonas Infections; Receptors, Cell Surface; Steroids; Up-Regulation; Young Adult

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Diabetes Mellitus; Humans; Infection Control; North America; Pseudomonas Infections; Quality Assurance, Health Care; Survival Analysis; Vitamin D; Vitamins

The annual prevalence of Aspergillus colonization (AC) and allergic bronchopulmonary aspergillosis (ABPA) has recently increased in pediatric patients with cystic fibrosis (CF). The reasons remain unclear although a number of factors have been suggested to be involved. This study was set up to investigate the association between potential predisposing factors, including new therapies recommended in CF, and the occurrence of AC or ABPA in children with CF.. The medical records of 85 children monitored regularly in the Pediatric Reference Centre for Cystic Fibrosis Care (RCCFC) of the University Hospital of Marseille (France) were analyzed from the first time they attended the RCCFC until either the occurrence of an end event, or their last visit to the RCCFC. Risk factors for AC or ABPA were analyzed by univariate and multivariate logistic regression.. Eight children developed ABPA and 18 had AC. In univariate analysis, ABPA was significantly associated with RhDNase therapy, sensitization to Alternaria and Candida, and a low body mass index (BMI). Multivariate analysis identified an independent association between low BMI and ABPA (OR = 10.6, 95% CI [2.2-51.8], P = 0.004), and for the first time, between long-term azithromycin therapy and AC (OR = 6.4, 95% CI [2.1-19.5], P = 0.001). This latter association might be explained by the inhibitory effect of azithromycin on both the recruitment and the activation of neutrophils, which represent the first-line defenses against Aspergillus.. The risk factors associated with AC and ABPA in children with CF identified in this comprehensive exploratory study now need to be confirmed in further prospective studies.

Topics: Adolescent; Alternaria; Aspergillosis, Allergic Bronchopulmonary; Aspergillus; Azithromycin; Body Mass Index; Candida; Child; Child, Preschool; Cystic Fibrosis; Deoxyribonuclease I; Female; France; Humans; Immunization; Immunoglobulin E; Infant; Male; Neutrophil Activation; Prevalence; Retrospective Studies; Risk Factors

To increase clinician adherence to prescribing guidelines for pulmonary medications in children with cystic fibrosis (CF).. Quality improvement project with multiple time series design.. The CF center at a tertiary care pediatric hospital in the United States.. Children with CF who were eligible to receive oral azithromycin, nebulized dornase alfa, or inhaled tobramycin sulfate based on prescribing guidelines for CF lung disease.. Evidence-based prescribing guidelines were designed by a local committee to reflect consensus recommendations from the CF Foundation. Clinicians and families were educated about guidelines. Adherence to prescribing guidelines was tracked using a local CF database and record reviews. Weekly meetings were used to highlight adherence failures and promote clinician accountability.. The rate of clinician adherence to prescribing guidelines.. One hundred seventy patients with CF were included. At the start of the project, the rate of clinician adherence to prescribing guidelines was 62%. After 3 months of the project, the rate of clinician adherence to prescribing guidelines was 87% (odds ratio = 4.6; 95% confidence interval, 3.0-7.0). The improvements in adherence to prescribing guidelines were sustained for 21 months of follow-up.. Educating clinicians about prescribing guidelines, sharing guidelines with families, and monitoring clinician adherence improve prescribing adherence to evidence-based recommendations.

Topics: Administration, Inhalation; Administration, Oral; Ambulatory Care; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Deoxyribonuclease I; Evidence-Based Medicine; Guideline Adherence; Hospitals, Pediatric; Humans; Ohio; Practice Patterns, Physicians'; Quality of Health Care; Tobramycin

Azithromycin (AZM) has shown promising results in the treatment of Pseudomonas aeruginosa chronic lung infections such as those occurring in cystic fibrosis (CF) patients. We evaluated the effect of hypermutation and alginate hyperproduction on the bactericidal activity and resistance development to AZM in P. aeruginosa biofilms. Strains PAO1, its microcA mutant (PAOMA), and their respective mutS-deficient hypermutable derivatives (PAOMS and PAOMSA) were used. Biofilms were incubated with several AZM concentrations for 1, 2, 4, or 7 days, and the numbers of viable cells were determined. During the first 2 days, AZM showed bactericidal activity for all the strains, but in extended AZM incubation for strain PAOMS and especially strain PAOMSA, a marked increased in the number of viable cells was observed, particularly at 4 microg/ml. Biofilms formed by the lineages recovered from the 7-day experiments showed enhanced AZM resistance. Furthermore, most of the independent lineages studied, including those obtained from biofilms treated with AZM concentrations as low as 0.5 microg/ml, showed MexCD-OprJ hyperexpression and mutations in nfxB. The role of nfxB mutation in AZM resistance was further confirmed through the characterization of nfxB and mexD knockout mutants. Results from this work show that, although AZM exhibits bactericidal activity against P. aeruginosa biofilms, resistant mutants are readily selected and that, furthermore, they frequently show cross-resistance to other unrelated antipseudomonal agents such as ciprofloxacin or cefepime but hypersusceptibility to others such as imipenem or tobramycin. Therefore, these results should help guide the selection of appropriate antipseudomonal therapies in CF patients under AZM maintenance treatment.

Topics: Anti-Bacterial Agents; Azithromycin; Bacterial Proteins; Biofilms; Cefepime; Cephalosporins; Ciprofloxacin; Cystic Fibrosis; DNA-Binding Proteins; Humans; Membrane Proteins; Membrane Transport Proteins; Microbial Sensitivity Tests; Mutation; MutS DNA Mismatch-Binding Protein; Pseudomonas aeruginosa; Transcription Factors

Since 2001, long-term, low-dose azithromycin treatment has been used for CF patients chronically infected with Pseudomonas aeruginosa in the Copenhagen CF centre. Our study investigates changes in incidence of colonization with Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis and changes in macrolide sensitivity in these microorganisms during azithromycin treatment.. CF patients treated continuously with azithromycin for at least 3 months were included. Results of microbiological examination, including phage typing results of S. aureus, obtained during treatment were compared to results obtained 2 years before treatment.. 70 patients (median age 29.1 years) treated for a median of 4 years (range 0.7-5.1) were included. Before treatment, 44 patients had at least one culture positive for S. aureus compared to 25 patients during treatment (p<0.01). Mean percentage of sputum samples with growth of S. aureus decreased from 12.1% (range 0-82.6%) before treatment to 6.1% (range 0-93.2) during treatment (p<0.0006). Prevalence's of H. influenzae and S. pneumoniae also decreased significantly. Fifteen of 214 isolates (7%) of S. aureus were macrolide resistant before treatment, increasing to 95 of 181 isolates (52.5%) during treatment (p<0.001). Macrolide resistant strains were found in 3 of 44 S. aureus colonized patients before treatment and in 11 of 25 patients at some time during treatment (p<0.03), all belonging to different phage types. First resistant S. aureus isolate was isolated after a median treatment duration of 1.5 years (range 0.3-2.9). No MRSA were isolated. Only 1 macrolide resistant isolate of M. catarrhalis was found during treatment. No macrolide resistance was found in H. influenzae or S. pneumoniae.. Long-term, low-dose treatment with azithromycin in CF patients leads to reduced prevalence of S. aureus, S. pneumoniae, and H. influenzae, but increased macrolide resistance in S. aureus. Reduction in the prevalence of S. aureus will make increasing macrolide resistance clinically insignificant in these patients.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Chronic Disease; Cystic Fibrosis; Denmark; Drug Resistance, Microbial; Haemophilus influenzae; Humans; Infant; Long-Term Care; Microbial Sensitivity Tests; Middle Aged; Moraxella catarrhalis; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Sputum; Staphylococcus aureus; Streptococcus pneumoniae; Young Adult

Anti-inflammatory properties of azithromycin (AZM) have been proposed as possible mechanisms of clinical beneficial effects in patients with cystic fibrosis (CF). Altered glutathione (GSH) transport in cystic fibrosis transmembrane regulator protein (CFTR)-deficient cells leads to the occurrence of oxidative stress that finally induces glutathione S-transferase (GST) activity. The present investigation was aimed to verify the effects of AZM on GST activity and expression in CF airway cells in vitro and in vivo. AZM exposure significantly decreased GSTT1 and GSTM1 mRNA and protein expression in IB3-1, restoring the levels to those observed in non-CF C38 cells, which also express lower levels of gamma-glutamyltransferase (GGT) activity than IB3-1. In another CF cell line, 2CFSMEo-, AZM produced 45% reduction in GSTT1 and GSTM1 mRNA levels. AZM reduced GST activity by approximately 25% and 40% in IB3-1 and 2CFSMEo- cells, respectively. GSTP1 was similarly expressed in all CF and non-CF cells and was unaffected by AZM. The anti-inflammatory cytokine IL-10 down-modulated GST activity at similar levels, supporting a link between GST inhibition and anti-inflammatory properties of AZM. In bronchoalveolar lavage fluid of CF mice homozygous for the F508 del mutation, GSTM1 protein levels were undetectable after AZM treatment. The association between increased GST expression and activity, together with its reversal by AZM treatment in vitro and in vivo, suggest novel antioxidant properties for this drug. The issue whether decreased GST activity may directly concur to anti-inflammatory properties of AZM or is rather a marker of the oxidative status of CF cells will require additional studies.

Topics: Animals; Anti-Inflammatory Agents; Azithromycin; Bronchoalveolar Lavage Fluid; Cell Line; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Female; Glutathione Transferase; Humans; Interleukin-8; Isoenzymes; Mice; Mice, Transgenic; Oxidation-Reduction; Respiratory Mucosa; Sulfhydryl Compounds; Tumor Necrosis Factor-alpha

Macrophages phagocyte pathogenic microorganisms and orchestrate immune responses by producing a variety of inflammatory mediators. The cystic fibrosis (CF) transmembrane conductance regulator chloride channel has been reported to be of pivotal importance for macrophage functions. The exact phenotype and role of macrophages in CF is still unknown. Alveolar and peritoneal macrophages were monitored in CF mice homozygous for the F508 del mutation and in wild-type control animals. Classical (M1) and alternative (M2) macrophage polarization and responses to LPS from Pseudomonas aeruginosa were investigated, and the effect of azithromycin was examined in both cell populations. We show that alveolar macrophage counts were 1.7-fold higher in CF as compared with wild-type mice. The macrophage-related chemokine, chemokine C-C motif ligand (CCL)-2, was found to be at least 10-fold more abundant in the alveolar space of mutant mice. Cell count and CCL-2 protein levels were also increased in the peritoneal cavity of CF mice. Both M1 and M2 macrophage polarization were significantly enhanced in alveolar and peritoneal cells from F508del-CF mice as compared with control animals. LPS-stimulated expression of proinflammatory mediators, such as nitric oxide synthase-2, IL-1beta, and CCL-2, was increased, whereas anti-inflammatory IL-10 expression was decreased in CF macrophages. Azithromycin, added to cell cultures at 1 mg/liter, significantly reduced proinflammatory cytokine expression (IL-1beta, CCL-2, TNF-alpha) in M1-induced CF and wild-type alveolar macrophages. Our findings indicate that CF macrophages are ubiquitously accumulated, and that these cells are polarized toward classical and alternative activation status. Azithromycin down-regulates inflammatory cytokine production by M1-polarized CF alveolar macrophages.

Topics: Animals; Anti-Bacterial Agents; Arginase; Azithromycin; Cells, Cultured; Chemokine CCL2; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytokines; Disease Models, Animal; Female; Immunity, Innate; Inflammation Mediators; Interleukin-10; Interleukin-1beta; Lipopolysaccharides; Macrophage Activation; Macrophages, Alveolar; Macrophages, Peritoneal; Mice; Mice, Transgenic; Mutation; Nitric Oxide Synthase Type II; Phenotype; Pseudomonas aeruginosa; Receptors, Immunologic; RNA, Messenger; Tumor Necrosis Factor-alpha

Azithromycin (AZM) has been used as an anti-inflammatory agent in the treatment of cystic fibrosis (CF), particularly those with chronic infection with P. aeruginosa (PA). To investigate mechanisms associated with the beneficial effects of AZM in CF, we examined bacterial load, cytokine levels, and clearance of inflammatory cells in CF mice infected with mucoid PA and treated with AZM.. Gut-corrected Cftr(tm1Unc)-TgN(FABPCFTR)#Jaw CF mice infected with an alginate-overproducing PA CF-isolate were treated with AZM or saline and examined for survival of animals, lung bacterial load, inflammation, cytokine levels, and apoptotic cells up to 5 days post-infection.. Administration of AZM (20 mg/kg) 24 h after the infection improved 5-day survival to 95% compared with treatment with saline (56%). AZM administration was associated with significant reductions in bacterial load, decreased lung inflammation, and increased levels of IFN-gamma. AZM increased macrophage clearance of apoptotic neutrophils from the lung.. Azithromycin enhances bacterial clearance and reduces lung inflammation by improving innate immune defense mechanisms in CF mice.

Topics: Alginates; Animals; Anti-Bacterial Agents; Apoptosis; Azithromycin; Biofilms; Bronchoalveolar Lavage Fluid; Cystic Fibrosis; Cytokines; Drug Resistance, Bacterial; Female; Lung; Mice; Neutrophils; Peroxidase; Pneumonia; Pseudomonas Infections; Respiratory Mucosa; Survival Analysis

Beneficial effects of azithromycin in cystic fibrosis (CF) have been reported, however, its mechanism of action remains unclear. The present study aimed at investigating the effect of azithromycin on CF airway epithelial cells.. Primary cultures of purified tracheal epithelial cells from F508del and normal homozygous mice were established. Responses to lipopolysaccharide from Pseudomonas aeruginosa (LPS, 0.1 microg/ml) on mRNA expression of neutrophil-related chemokines, pro- and anti-inflammatory cytokines were investigated in the presence or the absence of azithromycin (1 microg/ml).. CF airway epithelial cells showed upregulation of MIP-2 and KC responses to LPS, and azithromycin failed to downregulate these responses. In contrast, in CF cells, azithromycin increased KC and TNF-alpha expression under non-stimulated and LPS-stimulated conditions, respectively. In non-CF cells, the macrolide potentiated the LPS response on MIP-2 and on IL-10.. Airway epithelial cells contribute to the dysregulated immune processes in CF. Azithromycin rather stimulates cytokine expression in CF airway epithelial cells.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Cell Culture Techniques; Cells, Cultured; Cystic Fibrosis; Cytokines; Disease Models, Animal; Epithelial Cells; Mice; Mice, Inbred Strains; Neutrophils; RNA, Messenger; Trachea

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.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bacterial Proteins; Cystic Fibrosis; DNA, Bacterial; Drug Resistance, Bacterial; Erythromycin; Humans; Macrolides; Membrane Proteins; Methyltransferases; Microbial Sensitivity Tests; Molecular Sequence Data; Sequence Analysis, DNA; Streptococcal Infections; Streptococcus

Azithromycin (AZM) ameliorates lung function in cystic fibrosis (CF) patients. This macrolide has been suggested to have anti-inflammatory properties as well as other effects potentially relevant for therapy of CF. In this study, we utilized three CF (IB3-1, 16HBE14o- AS3, and 2CFSMEo-) and two isogenic non-CF (C38 and 16HBE14o- S1) airway epithelial cell lines to investigate whether AZM could reduce tumor necrosis factor alpha (TNF-alpha) mRNA and protein levels by real-time quantitative PCR analysis and an enzyme-linked immunosorbent assay (ELISA), respectively. We studied the effects on the DNA binding of NF-kappaB and specificity protein 1 (Sp1) by an ELISA. Non-CF cells express significantly lower TNF-alpha mRNA and protein levels than an isogenic CF cell line. In CF cells, AZM treatment causes a 30% reduction of TNF-alpha mRNA levels (P < 0.05) and a 45% decrease in TNF-alpha secretion (P < 0.05), reaching approximately the levels of the untreated isogenic non-CF cells. In CF cells, NF-kappaB and Sp1 DNA binding activities were also significantly decreased (about 45 and 60%, respectively; P < 0.05) after AZM treatment. Josamycin, a macrolide lacking clinically described anti-inflammatory effects, was ineffective. Finally, AZM did not alter the mRNA expression levels of interleukin-6, a proinflammatory molecule not differentially expressed in CF and isogenic non-CF cells. The results of our study support the anti-inflammatory activities of this macrolide, since we show that AZM reduced the levels of TNF-alpha and propose inhibitions of NF-kappaB and Sp1 DNA binding as possible mechanisms of this effect.

Topics: Anti-Bacterial Agents; Azithromycin; Cell Line; Cells, Cultured; Cystic Fibrosis; DNA; Epithelial Cells; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Interleukin-6; Josamycin; NF-kappa B; Respiratory Mucosa; RNA; Sp1 Transcription Factor; Tumor Necrosis Factor-alpha

Cystic fibrosis (CF) is associated with severe neutrophilic airway inflammation. We showed that moxifloxacin (MXF) inhibits IL-8 and MAPK activation in monocytic and respiratory epithelial cells. Azithromycin (AZM) and ciprofloxacin (CIP) are used clinically in CF. Thus we now examined effects of MXF, CIP, and AZM directly on CF cells. IB3, a CF bronchial cell line, and corrected C38 cells were treated with TNF-alpha, IL-1beta, or LPS with or without 5-50 microg/ml MXF, CIP, or AZM. IL-6 and IL-8 secretion (ELISA), MAPKs ERK1/2, JNK, p38, and p65 NF-kappaB (Western blot) activation were measured. Baseline IL-6 was sixfold higher in IB3 than C38 cells but IL-8 was similar. TNF-alpha and IL-1beta increased IL-6 and IL-8 12- to 67-fold with higher levels in IB3 than C38 cells post-TNF-alpha (P < 0.05). Levels were unchanged following LPS. Baseline phosphorylated form of ERK1/2 (p-ERK1/2), JNK, and NF-kappaB p65 were higher in IB3 than C38 cells (5-, 1.4-, and 1.4-fold), and following TNF-alpha increased, as did the p-p38, by 1.6- to 2-fold. MXF (5-50 microg/ml) and CIP (50 microg/ml), but not AZM, suppressed IL-6 and IL-8 secretion by up to 69%. MXF inhibited TNF-alpha-stimulated MAPKs ERK1/2, 46-kDa JNK, and NF-kappaB up to 60%, 40%, and 40%, respectively. In contrast, MXF did not inhibit p38 activation, implying a highly selective pretranslational effect. In conclusion, TNF-alpha and IL-1beta induce an exaggerated inflammatory response in CF airway cells, inhibited by MXF more than by CIP or AZM. Clinical trials are recommended to assess efficacy in CF and other chronic lung diseases.

Topics: Anti-Infective Agents; Aza Compounds; Azithromycin; Bronchi; Cell Line; Ciprofloxacin; Cystic Fibrosis; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Fluoroquinolones; Humans; Interleukin-1beta; Interleukin-6; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Moxifloxacin; NF-kappa B; Phosphorylation; Quinolines; Tumor Necrosis Factor-alpha

Maintenance azithromycin therapy may improve pulmonary function in patients with cystic fibrosis (CF) with Pseudomonas aeruginosa infection because of its antiinflammatory properties. However, azithromycin therapy might increase macrolide resistance in Staphylococcus aureus cultured from respiratory secretions. We studied the emergence of macrolide resistance in S. aureus and correlated this to pulmonary function decline in pediatric patients with CF on daily azithromycin therapy.. Respiratory cultures of 100 patients with CF were analyzed for S. aureus colonization and its resistance pattern before and during 3 years after initiation of azithromycin maintenance therapy. Mean annual change in forced expiratory volume as percent of predicted (FEV1 %) was calculated to compare pulmonary function before and after azithromycin therapy.. Staphylococcal colonization did not significantly decrease after initiation of azithromycin (50% versus 48%). Before start of therapy, 10% of patients with staphylococcal colonization had macrolide-resistant strains. Staphylococcal resistance increased to 83% in the first year; 97% in the second and 100% in the third year after initiation of azithromycin therapy (P < 0.001). Half of macrolide-resistant S. aureus comprised the macrolide-lincosamide-streptogramin phenotype. Percent forced expiratory volume in 1 second improved in the first year after initiation of azithromycin (mean annual change: -4.75% before versus +3.09% after initiation; P < 0.01) but decreased during the second and third years after initiation (-5.15% and -3.65%, respectively). Emergence of macrolide-resistant S. aureus was not related to pulmonary function decline.. Maintenance azithromycin therapy in patients with CF leads to macrolide resistance in nearly all S. aureus carriers. Pulmonary function improvement after initiation of azithromycin therapy seems to be temporary and appears not to be related to macrolide resistance of S. aureus.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Cystic Fibrosis; Drug Resistance; Drug Resistance, Microbial; Humans; Infant; Lung; Macrolides; Pseudomonas aeruginosa; Pseudomonas Infections; Staphylococcal Infections; Staphylococcus aureus

Induction of ATP Binding Cassette (ABC) proteins involved in chloride transport has been proposed as a possible mechanism of the beneficial effects of azithromycin (AZM) in cystic fibrosis (CF) patients. This study focused on the effects of AZM on mRNA and protein expression of Multidrug Resistance-associated Protein 1 (MRP1) and Multidrug Resistance Protein 1 (MDR1) by real-time quantitative PCR, flow cytometry and gene reporter assays in two CF and two isogenic non-CF airway epithelial cell lines. We detected higher levels of MRP1 and lower levels of MDR1 mRNA in CF versus non-CF cells while both proteins were not differentially expressed. After AZM treatment we found modest differences in MRP1 and MDR1 mRNA expression while protein levels were unaffected. The ability of AZM to regulate MRP1 promoter transcriptional activity was excluded by gene reporter assays. Our data do not support the hypothesis of induction of ABC transporters by AZM.

Topics: Anti-Bacterial Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Azithromycin; Bronchi; Cell Line; Cystic Fibrosis; Gene Expression; Humans; Multidrug Resistance-Associated Proteins; Respiratory Mucosa; RNA, Messenger

Several studies have reported clinical improvements in cystic fibrosis (CF) patients on macrolide antibiotics although the mechanism of action remains unclear. We conducted an open-label study of azithromycin (500 mg daily for 2 weeks) in 9 adult CF patients to explore 3 possible mechanisms: up-regulation of the multi-drug resistance (MDR) or cystic fibrosis transmembrane regulator (CFTR) proteins, correction of epithelial ion transport and reduced bacterial adherence. End-points included nasal potential difference (PD) measurements, nasal epithelial MDR and CFTR mRNA levels and Pseudomonas aeruginosa adherence to nasal epithelium. Forced expiratory volume in the 1st second (FEV(1)) increased significantly after 2 weeks of azithromycin (pre- 41.1 [5.0]%; post- 44.6 [5.8]%; P<0.05), although improvements in forced vital capacity (FVC) did not reach significance (pre- 61.3 [4.0]%; post- 67.1 [5.4]%, NS). Before treatment all subjects had nasal PD measurements characteristic of CF. Treatment led to no significant group differences in any measures of either sodium absorption or chloride secretion. Neither CFTR nor MDR mRNA levels had altered significantly and the adherence of P. aeruginosa did not decrease. We conclude that these are unlikely to be significant contributing mechanisms accounting for the consistent beneficial results observed in clinical trials of macrolides in CF.

Topics: Adult; Anti-Bacterial Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azithromycin; Cell Adhesion; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Forced Expiratory Volume; Humans; Ion Transport; Male; Nasal Mucosa; Pseudomonas aeruginosa; RNA, Messenger; Up-Regulation; Vital Capacity

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.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Cystic Fibrosis; Drug Resistance, Bacterial; Female; Haemophilus; Humans; Infant; Logistic Models; Macrolides; Male; Microbial Sensitivity Tests; Sputum; Staphylococcus aureus; Time Factors

We aimed at identifying molecular mechanisms for anti-inflammatory effects of azithromycin (AZM) suggested by clinical evidences. IL-8 expression and DNA binding activity of two key pro-inflammatory transcription factors (TF), NF-kappaB and AP-1, were investigated in cystic fibrosis (CF) and isogenic non-CF airway epithelial cell lines. AZM reduced about 40% of IL-8 mRNA and protein expression (n=9, p=0.02, and n=4, p=0.00011) in CF cells reaching the levels of non-CF cells. In the presence of AZM we found about 50% and 70% reduction of NF-kappaB and AP-1 DNA binding, respectively (n=3, p=0.01, and n=3, p=0.0017), leading to levels of non-CF cells. The relevance of NF-kappaB and AP-1 in regulating IL-8 promoter transcriptional activity was demonstrated by gene reporter assays (n=4, p=8.54x10(-7), and n=4, p=6.45x10(-6)). Our data support the anti-inflammatory effects of AZM in CF cells, indicating inhibition of transcription of pro-inflammatory genes as possible mechanism, thus providing a rationale for the possible use of specific TF inhibitors for therapy.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Cell Line; Cystic Fibrosis; Dose-Response Relationship, Drug; Epithelial Cells; Humans; Interleukin-8; NF-kappa B; Transcription Factor AP-1

Inflammation plays a critical role in lung disease development and progression in cystic fibrosis. Azithromycin is used for the treatment of cystic fibrosis lung disease, although its mechanisms of action are poorly understood. We tested the hypothesis that azithromycin modulates lung inflammation in cystic fibrosis mice.. We monitored cellular and molecular inflammatory markers in lungs of cystic fibrosis mutant mice homozygous for the DeltaF508 mutation and their littermate controls, either in baseline conditions or after induction of acute inflammation by intratracheal instillation of lipopolysaccharide from Pseudomonas aeruginosa, which would be independent of interactions of bacteria with epithelial cells. The effect of azithromycin pretreatment (10 mg/kg/day) given by oral administration for 4 weeks was evaluated.. In naive cystic fibrosis mice, a spontaneous lung inflammation was observed, characterized by macrophage and neutrophil infiltration, and increased intra-luminal content of the pro-inflammatory cytokine macrophage inflammatory protein-2. After induced inflammation, cystic fibrosis mice combined exaggerated cellular infiltration and lower anti-inflammatory interleukin-10 production. In cystic fibrosis mice, azithromycin attenuated cellular infiltration in both baseline and induced inflammatory condition, and inhibited cytokine (tumor necrosis factor-alpha and macrophage inflammatory protein-2) release in lipopolysaccharide-induced inflammation.. Our findings further support the concept that inflammatory responses are upregulated in cystic fibrosis. Azithromycin reduces some lung inflammation outcome measures in cystic fibrosis mice. We postulate that some of the benefits of azithromycin treatment in cystic fibrosis patients are due to modulation of lung inflammation.

Topics: Animals; Anti-Inflammatory Agents; Azithromycin; Chemokine CXCL2; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Interleukin-10; Lipopolysaccharides; Lung; Macrophages; Mice; Mice, Mutant Strains; Monokines; Neutrophil Infiltration; Pneumonia; Tumor Necrosis Factor-alpha

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Humans

In cystic fibrosis (CF), chronic endobronchial infection with Pseudomonas aeruginosa is a serious complication. Macrolides can increase lung function and weight in patients, and reduce exacerbations.. In 2001, we introduced long-term, low-dose azithromycin (AZ) treatment as an integral part of our routine treatment of these patients. Our study is an observational cohort study of all CF patients with chronic P. aeruginosa infection in our CF center comparing clinical parameters of the patients 12 months prior to treatment with the same values during 12 months of treatment.. 45 patients (27 men, median age 29 years) completed 1-year treatment. Median weight increased from 63.1 kg in the pre-treatment period to 63.9 kg during treatment (p=0.01). Median slope of decline in lung function increased from pre-treatment FEV1 -4.1% and FVC -3.0% to +0.8% (p<0.001) and +1.6% (p=0.01), respectively. 90% of sputum samples contained mucoid P. aeruginosa before treatment, decreasing to 81% during treatment (p=0.003). Median CRP decreased from 6.2 mmol/l to 5.8 mmol/l (ns).. Long-term, low-dose AZ treatment in adult CF patients with chronic P. aeruginosa infection is safe and reduces the decline in lung function, increases weight, and reduces the percentage of mucoid strains of P. aeruginosa in sputum samples.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Chronic Disease; Cystic Fibrosis; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Observation; Pseudomonas aeruginosa; Pseudomonas Infections; Sputum; Treatment Outcome

Macrolides is effective therapy in patients with cystic fibrosis (CF). We describe a girl with CF given long-term azithromycin who died of rapidly progressive lung disease. She was found to have rising titers of mycoplasma serology, suggesting a possible causative role of a resistant mycoplasma infection. Mycoplasma infection should be considered in CF patients who are deteriorating, even if they are being treated with macrolides, to which these organisms are usually susceptible.

Topics: Adolescent; Anti-Bacterial Agents; Antibodies, Bacterial; Azithromycin; Cystic Fibrosis; Disease Progression; Fatal Outcome; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Mycoplasma pneumoniae; Pneumonia, Mycoplasma; Sputum

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Humans; Male; Pseudomonas Infections

There is considerable interest in the use of azithromycin for the treatment of lung disease in patients with cystic fibrosis (CF). Although its mechanism of action as an inhibitor of bacterial protein synthesis has been well-established, it is less clear how azithromycin ameliorates the lung disease associated with Pseudomonas aeruginosa, which is considered to be resistant to the drug. We tested the effects of azithromycin on clinical isolates (CIs) from CF patients and compared them with laboratory reference strains to establish how this drug might interfere with the production of bacterial virulence factors that are relevant to the pathogenesis of airway disease in CF patients. Azithromycin inhibited P aeruginosa PAO1 protein synthesis by 80%, inhibiting bacterial growth and the expression of immunostimulatory exoproducts such as pyocyanin, as well as the gene products necessary for biofilm formation. In contrast, the effects of azithromycin on CIs of P aeruginosa were much more variable, due in large part to their slow growth and limited exoproduct expression. Culture supernatants for two of three clinical strains induced appreciable CXCL8 expression from cultured epithelial cells. Azithromycin treatment of the organisms inhibited 65 to 70% of this induction; azithromycin had no direct effect on the ability of either normal cells or CF epithelial cells to produce CXCL8. Azithromycin does decrease the P aeruginosa synthesis of immunostimulatory exoproducts and is likely to be most effective against planktonic, actively growing bacteria. This effect is less predictable against CIs than the prototypic strain PAO1.

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Humans; Pseudomonas aeruginosa

Macrolides are accumulated in phagocytes, partially via an active transport system; the membrane carrier is not identified but many data indicate a link with the P-glycoprotein family which includes the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. We have used two epithelial cell lines which express either wild-type (N cells) or mutated (homozygous deltaF508) (F cells) CFTR to study the cellular accumulation of two macrolides (azithromycin and roxithromycin). Adherent cells were incubated with the radiolabeled drugs before extensive washings and counting. Azithromycin was better (about 2-fold) accumulated in F cells up to 60 min but then plateaued, whereas accumulation continued without saturation over 3 hours in N cells. Roxithromycin was also better (1.5-fold) accumulated in F cells at 15 and 30 min, but there were no differences at further incubation times. Macrolide efflux from loaded N and F cells, and the susceptibilities of the carrier systems (entry and efflux) to various pharmacologic agents were similar to those previously observed with phagocytes. These data suggest that the macrolide carriers (for entry and efflux) are not strictly specific for phagocytes and that the CFTR protein plays a role in macrolide uptake.

Topics: Analysis of Variance; Azithromycin; Case-Control Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Fetus; Humans; Mutation; Pharmacogenetics; Regression Analysis; Respiratory Mucosa; Roxithromycin; Sensitivity and Specificity; Trachea

Azithromycin is used for the treatment of cystic fibrosis lung disease, although its mechanisms of action are not completely understood. Besides its antiinflammatory and antimicrobial activities, one possibility could be the overexpression induction of the multidrug resistance-associated protein (MRP), which could affect chloride transport, thus overcoming the ion transport defect of cystic fibrosis. Seven patients were evaluated before and after 4 weeks of azithromycin treatment (500 mg once daily). Ion transport was studied in vivo by measuring nasal potential difference (NPD). MRP mRNA expression was studied in nasal cells by an internal standard-based semiquantitative RT-PCR assay. NPD was consistent with cystic fibrosis before treatment. After azithromycin treatment, sodium transport was still impaired, whereas a significant increase in chloride conductance was observed (p = 0.03). A significant direct correlation was found between MRP mRNA expression levels and NPD chloride response after azithromycin treatment (p = 0.04, r = 0.78). In conclusion, azithromycin may induce MRP overexpression and restore chloride conductance in the airways of cystic fibrosis patients. These findings suggest a new potential role of azithromycin in the treatment of cystic fibrosis pulmonary disease, i.e. the possibility to upregulate proteins whose function may, at least in part, compensate for the basic defect of cystic fibrosis.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA, Bacterial; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Ion Transport; Long-Term Care; Male; Multidrug Resistance-Associated Proteins; Nasal Mucosa; Probability; Prospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Severity of Illness Index; Statistics, Nonparametric; Treatment Outcome

Topics: Azithromycin; Bacterial Adhesion; Bronchoalveolar Lavage Fluid; Cystic Fibrosis; Humans; Microbial Sensitivity Tests; Mucins; Pseudomonas aeruginosa

Topics: Anti-Bacterial Agents; Azithromycin; Cystic Fibrosis; Humans; Maximal Expiratory Flow Rate; Patient Selection; Randomized Controlled Trials as Topic; Research Design

The number of adults with cystic fibrosis (CF) is increasing. They are striving for independence and a fulfilling life with focus on career, relationships, education and finances at a time when lung function is likely to be declining and complications of this multi-system disease are increasing. Maintaining the quality and improving the duration of life are continuing challenges for the -clinician and the patient. Increased hope and greater expectations have been provided by a number of recent clinical advances and active research into novel treatments, including gene therapy. There has been increased recognition of the necessity for early diagnosis, adequate monitoring and effective intervention for complications such as diabetes and osteoporosis. Research into multi-resistant bacteria and clonal strains of Pseudomonas aeruginosa is ongoing and attention has focused on infection control policies. Although more high-level evidence is required on many issues confronting people with CF, a considerable effort has been made over the last decade to provide a more evidence-based approach to therapy with a number of large controlled clinical trials. For the adult with CF, there are also more decisions to be made. There is focus on reproductive health, with most couples enjoying the real possibility of having children. For those with advanced disease, the option for lung transplantation is well established. Maintenance of quality care will require adequate planning, effective transition programmes from paediatric to adult care, specialized training for doctors, nurses and allied health professionals and the allocation of sufficient resources to accommodate the inevitable increase in patient numbers.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Clinical Trials as Topic; Cystic Fibrosis; Humans; Lung Diseases; Osteoporosis; Pseudomonas Infections

A number of studies have suggested that the non-antimicrobial actions of macrolide antibiotics may be valuable in treating patients with cystic fibrosis. The use of long-term macrolide antibiotics for the management of CF patients colonised by Pseudomonas aeruginosa and progressive pulmonary disease was introduced into our clinic in 1997. A retrospective study was undertaken to assess of the impact of this therapy.. Twenty patients with progressive pulmonary disease (>10% fall in FEV(1) over 12 months despite optimising conventional therapy) were commenced on Azithromycin, 250 mg daily during a 21-month period. At the time of assessment they had remained on therapy for a mean of 0.9 years. Changes in lung function, weight, body mass index (BMI) and frequency of pulmonary exacerbations were assessed. A group of 20 patients with stable lung function and matched as far as possible for age and sex was identified for comparison.. Pulmonary function increased significantly in the Azithromycin group with FEV1% predicted increasing from a mean of 50.2-59.1% (P=0.001) while FVC% predicted increase from 64.5 to 76.1% (P=0.002). There was small but non-significant fall in lung function in the comparison group. Body mass index increased by a mean of 1.1 in the Azithromycin group but remained unchanged in the comparison group. The number of pulmonary exacerbations requiring intravenous antibiotics declined by 48.3% in macrolide treated subjects compared to the pre-treatment period (P<0.025); frequency of exacerbations in the control group was unchanged.. Long-term Azithromycin treatment in patients with progressive deterioration in lung function appears to have led to an improvement in pulmonary function, increased body mass index and decreased the frequency of pulmonary exacerbations requiring intravenous antibiotics.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Body Mass Index; Bronchial Diseases; Chronic Disease; Cystic Fibrosis; Disease Progression; Drug Administration Schedule; England; Female; Forced Expiratory Volume; Humans; Long-Term Care; Male; Predictive Value of Tests; Pseudomonas Infections; Recurrence; Retrospective Studies; Sputum; Treatment Outcome; Vital Capacity; Weight Gain

Six strains of Staphylococcus aureus isolated from cystic fibrosis patients after treatment with azithromycin were cross-resistant to azithromycin and erythromycin. None of the isolates contained erm or msr(A) genes, but they all carried either A2058G/U or A2059G mutations within the rrl genes, with a majority of the rRNA copies bearing the mutation. One strain displayed an additional mutation in the rplV gene, encoding the L22 ribosomal protein.

Topics: Anti-Bacterial Agents; Azithromycin; Bacterial Proteins; Cystic Fibrosis; DNA, Bacterial; Drug Resistance; Erythromycin; Genes, Bacterial; Humans; Membrane Transport Proteins; Methyltransferases; Microbial Sensitivity Tests; Mutation; Oligonucleotide Probes; Reverse Transcriptase Polymerase Chain Reaction; Ribosomes; Staphylococcal Infections; Staphylococcus aureus

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Female; Humans; Male; Pseudomonas Infections; Respiratory Function Tests; Time Factors

Topics: Anti-Bacterial Agents; ATP-Binding Cassette Transporters; Azithromycin; Cystic Fibrosis; Humans; Multidrug Resistance-Associated Proteins; Up-Regulation

Pseudomonas aeruginosa is a saprophyte opportunistic bacteria which frequently colonizes the respiratory tract of patients presenting a severe chronic bronchitis pathology. Secreting a number of exotoxins and enzymes inducing an inflammation and necrosing of the surrounding tissues, it provokes irreversible pulmonary lesions. Different experimental in vitro works evidenced macrolides activity on the production and/or secretion of these factors, with a diminution of elastase, protease, lecithinase and D-nase synthesis. Among the macrolides, azithromycin seems to have the most pronounced activity. In vivo, some patients suffering from bronchiolitis or cystic fibrosis have been clinically improved with a treatment using erythromycin, or clarithromycin or azithromycin. These very preliminary results demand to be confirmed but the macrolides could allow a decrease of Pseudomonas aeruginosa pathogenicity and thus stop the deterioration of pulmonary functions.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiolitis; Cystic Fibrosis; Humans; In Vitro Techniques; Pseudomonas aeruginosa; Pseudomonas Infections; Virulence