zithromax and Inflammation

The rapid advancement of the COVID-19 pandemic has prompted an accelerated pursuit to identify effective therapeutics. Stages of the disease course have been defined by viral burden, lung pathology, and progression through phases of the immune response. Immunological factors including inflammatory cell infiltration and cytokine storm have been associated with severe disease and death. Many immunomodulatory therapies for COVID-19 are currently being investigated, and preliminary results support the premise of targeting the immune response. However, because suppressing immune mechanisms could also impact the clearance of the virus in the early stages of infection, therapeutic success is likely to depend on timing with respect to the disease course. Azithromycin is an immunomodulatory drug that has been shown to have antiviral effects and potential benefit in patients with COVID-19. Multiple immunomodulatory effects have been defined for azithromycin which could provide efficacy during the late stages of the disease, including inhibition of pro-inflammatory cytokine production, inhibition of neutrophil influx, induction of regulatory functions of macrophages, and alterations in autophagy. Here we review the published evidence of these mechanisms along with the current clinical use of azithromycin as an immunomodulatory therapeutic. We then discuss the potential impact of azithromycin on the immune response to COVID-19, as well as caution against immunosuppressive and off-target effects including cardiotoxicity in these patients. While azithromycin has the potential to contribute efficacy, its impact on the COVID-19 immune response requires additional characterization so as to better define its role in individualized therapy.

Topics: Azithromycin; COVID-19 Drug Treatment; Cytokines; Humans; Immunomodulation; Inflammation; Neutrophils; Pandemics; SARS-CoV-2

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

Acute wheezing episodes are frequent in young children and are associated with high morbidity and healthcare utilization. The role of respiratory viruses in triggering acute wheezing is well known. There is also accumulating evidence that airway bacteria, either alone or as part of bacteria-virus interaction, are important determinants of acute asthma exacerbations. Targeting airway bacteria with antibiotics to reduce the severity of acute wheezing episodes and prevent recurrent wheezing among preschool children has been recently evaluated in three randomized, double-blind, placebo-controlled trials. The results of these studies are controversial. An interventional approach with azithromycin in young children during acute wheezing episodes cannot be generically incorporated into clinical practice, due to the potential consequences of widespread use of antibiotics in such a common clinical setting. This intervention may be reserved for children with really severe, recurrent wheezing episodes. Future research should focus on risk factors that facilitate acquisition of bacterial airway infection in young children and better understanding how virus and bacteria interact with each other during wheezing attacks. Identifying objective biomarkers that may direct the treatment to specific groups of children may represent a significant step forward in the clinical approach of acute wheezing.

Topics: Acute Disease; Anti-Bacterial Agents; Azithromycin; Bacterial Infections; Child, Preschool; Clinical Trials as Topic; Dysbiosis; Humans; Inflammation; Microbial Interactions; Microbiota; Patient Selection; Recurrence; Respiratory Sounds; Respiratory Tract Infections; Severity of Illness Index; Virus Diseases

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

Azithromycin has a well-characterized bacteriostatic activity. However, it also has a robust immunomodulatory effect that has proven beneficial in a variety of chronic illnesses. This effect results in decreased production of pro-inflammatory cytokines in the acute phase and promotes resolution of chronic inflammation in the later phases. Specifically, azithromycin has direct activity on airway epithelial cells to maintain their function and reduce mucus secretion. These characteristics have resulted in the use of azithromycin in the management of a variety of chronic lung diseases including chronic obstructive pulmonary disease, cystic fibrosis (CF), non-CF bronchiectasis, bronchiolitis obliterans syndrome, diffuse panbronchiolitis, and asthma. In this review, we present the evidence supporting the role of azithromycin in these conditions with an emphasis on the clinical aspects for the practicing physician.

Topics: Anti-Bacterial Agents; Azithromycin; Cytokines; Drug Resistance, Bacterial; Epithelial Cells; Humans; Immunomodulation; Inflammation; Lung Diseases

The number of senile patients with chronic obstructive pulmonary disease (COPD) has recently increased due to an increase in life expectancy, the habit of smoking and the inhalation of toxic particles. COPD exacerbations are caused by airway bacterial and viral infections, as well as the inhalation of oxidative substrates. COPD exacerbations are associated with the worsening of symptoms and quality of life, as well as an increased mortality rate. Several drugs, including long-acting anti-cholinergic agents, long-acting β(2)-agonists and inhaled corticosteroids, have been developed to improve symptoms in COPD patients and to prevent COPD exacerbations. Treatment with macrolide antibiotics has been reported to prevent COPD exacerbations and improve patient quality of life and symptoms, especially in those patients who have frequent exacerbations. In addition to their antimicrobial effects, macrolides have a variety of physiological functions, such as anti-inflammatory and anti-viral effects, reduced sputum production, the inhibition of biofilm formation and the inhibition of bacterial virulence factor production. These unique activities may relate to the prevention of exacerbations in COPD patients who receive macrolides. Herein, we review the inhibitory effects that macrolides have on COPD exacerbations and explore the possible mechanisms of these effects.

Topics: Anti-Inflammatory Agents; Antiviral Agents; Azithromycin; Biofilms; Bronchodilator Agents; Clinical Trials as Topic; Cytokines; Humans; Inflammation; Japan; Macrolides; Mucus; Oxygen; Placebos; Pulmonary Disease, Chronic Obstructive; Quality of Life; Retrospective Studies; Smoking

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

It has been recognized for more than 20 years that the macrolides have immunomodulatory effects that are beneficial for those suffering from chronic pulmonary inflammatory syndromes, such as diffuse panbronchiolitis, cystic fibrosis, asthma and bronchiectasis. The macrolides have consistently been associated with decreased length of stay and mortality when used alone or in combination with beta-lactam antibiotics. This effect can be demonstrated against combinations consisting of beta-lactams and other antibiotics active against 'atypical chest pathogens' when treating community-acquired pneumonia (CAP) in hospitalized patients. As such, it appears that the macrolides' effects in CAP patients are more than just antibacterial in nature. AIMS OF THIS REVIEW: This review aims: to give the reader information on the background areas described, as well as related areas; to review the CAP benefits with macrolides and how they may be related to the immunomodulatory properties they demonstrate, albeit in a shorter period of time than previously demonstrated with chronic pulmonary disorders; to use ex vivo data to support these extrapolations.. A literature search using Medline was conducted from 1966 onwards, searching for articles with relevant key words such as macrolide, diffuse panbronchiolitis, community-acquired pneumonia, biofilm, immunomodulation, cystic fibrosis, erythromycin, clarithromycin, roxithromycin and azithromycin, bronchiectasis and asthma. When appropriate, additional references were found from the bibliographies of identified papers of interest. Any relevant scientific conference proceedings or medical texts were checked when necessary.. (1) Research into macrolide immunomodulation for chronic pulmonary disorders demonstrates consistent positive effects, although of types other than seen with diffuse panbronchiolitis. These effects, together with their inhibitory activity on biofilms, have the potential to make them a useful option. (2) The benefits for CAP are consistent, and higher when a macrolide is given with another atypical agent than if the other atypical agent is given alone, suggesting a non-antibacterial benefit. (3) Recent research of the immunomodulatory properties of azithromycin imply that azithromycin may have a previously unknown short-term biphasic effect on inflammation modulation: enhancement of host defence mechanisms shortly after initial administration followed by curtailment of local infection/inflammation in the following period. (4) Additional in vivo research is needed prior to developing any firm conclusions.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Chronic Disease; Clarithromycin; Community-Acquired Infections; Erythromycin; Humans; Inflammation; Macrolides; Respiratory Tract Infections

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

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

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

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

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

Azithromycin mass drug administration (MDA) could reduce child mortality. However, macrolide resistance, which has generally been reported to develop after whole-community MDA for trachoma control, is a concern, and it has less commonly been studied in the context of treating children to reduce mortality. Here, we report on macrolide resistance after biannual azithromycin MDA at the Malawi site of the MORDOR study.. In the MORDOR cluster-randomised trial in Malawi, 30 communities in Mangochi District were randomly selected. Communities were randomly assigned to receive azithromycin or placebo by simple randomisation without stratification. Children aged 1-59 months were administered azithromycin 20 mg/kg or placebo as an oral suspension biannually for a total of four treatments in 2015-17. 1200 children (40 children per community) were randomly selected for nasopharyngeal swabs at baseline, 12 months (6 months after the second treatment visit), and 24 months (6 months after the fourth treatment visit). Samples were processed to culture. These findings support previous evidence from trachoma MDA programmes and suggest that monitoring of macrolide resistance should remain a key component of azithromycin interventions for reducing child mortality.. Bill & Melinda Gates Foundation.. Our results indicate that non-invasive local LIPUS therapy attenuated heart fibrosis and dysfunction in diabetic mice and the effect could be largely preserved at least 12 weeks after suspending LIPUS stimulation. LIPUS ameliorated diabetic heart fibrosis by inhibiting ACE-mediated NOX4-associated oxidative stress and NLRP3 inflammasome activation in cardiac fibroblasts. Our study may provide a novel therapeutic approach to hamper the progression of diabetic heart fibrosis.

Topics: Acoustics; Adsorption; Angiotensin II; Animals; Anti-Bacterial Agents; Azithromycin; Calcium; Carbon; Charcoal; Child; Chlorides; Copper; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Dopamine; Dopamine Plasma Membrane Transport Proteins; Drug Resistance, Bacterial; Ecosystem; Epigenesis, Genetic; Female; Fibroblasts; Fibrosis; Gallium Radioisotopes; Heterozygote; Hot Temperature; Humans; Hydrogen-Ion Concentration; Inflammasomes; Inflammation; Kinetics; Macrolides; Magnetic Resonance Imaging; Malawi; Male; Mass Drug Administration; Methylene Blue; Mice; Neuroendocrine Tumors; NLR Family, Pyrin Domain-Containing 3 Protein; Octreotide; Organometallic Compounds; Oxidative Stress; Phenotype; Positron-Emission Tomography; Prevalence; Prognosis; Rats; Receptors, Somatostatin; Retrospective Studies; Rivers; Streptococcus pneumoniae; Trachoma; Water Pollutants, Chemical; Zinc Compounds

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

Because transmission of ocular strains of Chlamydia trachomatis is greatest among preschool-aged children, limiting azithromycin distributions to this age group may conserve resources and result in less antimicrobial resistance, which is a potential advantage in areas with hypoendemic trachoma and limited resources.. To determine the efficacy of mass azithromycin distributions to preschool-aged children as a strategy for trachoma elimination in areas with hypoendemic disease.. In this cluster randomized clinical trial performed from November 23, 2014, until July 31, 2017, thirty rural communities in Niger were randomized at a 1:1 ratio to biannual mass distributions of either azithromycin or placebo to children aged 1 to 59 months. Participants and study personnel were masked to treatment allocation. Data analyses for trachoma outcomes were performed from October 19, 2021, through June 10, 2022.. Every 6 months, a single dose of either oral azithromycin (20 mg/kg using height-based approximation for children who could stand or weight calculation for small children) or oral placebo was provided to all children aged 1 to 59 months.. Trachoma was a prespecified outcome of the trial, assessed as the community-level prevalence of trachomatous inflammation-follicular and trachomatous inflammation-intense through masked grading of conjunctival photographs from a random sample of 40 children per community each year during the 2-year study period. A secondary outcome was the seroprevalence of antibodies to C trachomatis antigens.. At baseline, 4726 children in 30 communities were included; 1695 children were enrolled in 15 azithromycin communities and 3031 children were enrolled in 15 placebo communities (mean [SD] proportions of boys, 51.8% [4.7%] vs 52.0% [4.2%]; mean [SD] age, 30.8 [2.8] vs 30.6 [2.6] months). The mean coverage of study drug for the 4 treatments was 79% (95% CI, 75%-83%) in the azithromycin group and 82% (95% CI, 79%-85%) in the placebo group. The mean prevalence of trachomatous inflammation-follicular at baseline was 1.9% (95% CI, 0.5%-3.5%) in the azithromycin group and 0.9% (95% CI, 0-1.9%) in the placebo group. At 24 months, trachomatous inflammation-follicular prevalence was 0.2% (95% CI, 0-0.5%) in the azithromycin group and 0.8% (95% CI, 0.2%-1.6%) in the placebo group (incidence rate ratio adjusted for baseline: 0.18 [95% CI, 0.01-1.20]; permutation P = .07).. The findings of this trial do not show that biannual mass azithromycin distributions to preschool-aged children were more effective than placebo, although the underlying prevalence of trachoma was low. The sustained absence of trachoma even in the placebo group suggests that trachoma may have been eliminated as a public health problem in this part of Niger.. ClinicalTrials.gov Identifier: NCT02048007.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Chlamydia trachomatis; Gonorrhea; Humans; Infant, Newborn; Infant, Newborn, Diseases; Inflammation; Male; Niger; Prevalence; Seroepidemiologic Studies; Trachoma

Neutrophilic inflammation is believed to contribute to the airway obstruction and remodelling in equine asthma. Azithromycin, an antibiotic with immunomodulatory properties, reduces pulmonary neutrophilia and hyper-responsiveness in human asthmatics and decreases airway remodelling in rodent models of asthma. It was therefore hypothesised that azithromycin would improve lung function, mucus accumulation and central airway remodelling by decreasing luminal neutrophilia in severe equine asthma. The effects of a 10-day treatment with either azithromycin or ceftiofur, an antimicrobial without immune-modulating activity, were assessed using a blind, randomised, crossover design with six severe asthmatic horses in clinical exacerbation. Lung function, tracheal mucus accumulation, tracheal wash bacteriology, bronchial remodelling, airway neutrophilia and mRNA expression of proinflammatory cytokines (interleukin (IL)-8, IL-17A, IL-1β, tumour necrosis factor-α) in bronchoalveolar lavage fluid were evaluated. Azithromycin decreased the expression of IL-8 (P=0.03, one-tailed) and IL-1β (P=0.047, one-tailed) but failed to improve the other variables evaluated. Ceftiofur had no effect on any parameter. The reduction of neutrophilic chemoattractants (IL-8, IL-1β) justifies further efforts to investigate the effects of a prolonged treatment with macrolides on airway neutrophilia and remodelling. The lack of efficacy of ceftiofur suggests that severe equine asthma should not be treated with antibiotics at first-line therapy.

Topics: Airway Remodeling; Animals; Asthma; Azithromycin; Cross-Over Studies; Female; Horse Diseases; Horses; Immunologic Factors; Inflammation; Lung; Male; Mucus; Respiratory Function Tests; Trachea

Azithromycin (AZM) reduces pulmonary inflammation and exacerbations in patients with COPD having emphysema. The antimicrobial effects of AZM on the lower airway microbiome are not known and may contribute to its beneficial effects. Here we tested whether AZM treatment affects the lung microbiome and bacterial metabolites that might contribute to changes in levels of inflammatory cytokines in the airways.. 20 smokers (current or ex-smokers) with emphysema were randomised to receive AZM 250 mg or placebo daily for 8 weeks. Bronchoalveolar lavage (BAL) was performed at baseline and after treatment. Measurements performed in acellular BAL fluid included 16S rRNA gene sequences and quantity; 39 cytokines, chemokines and growth factors and 119 identified metabolites. The response to lipopolysaccharide (LPS) by alveolar macrophages after ex-vivo treatment with AZM or bacterial metabolites was assessed.. Compared with placebo, AZM did not alter bacterial burden but reduced α-diversity, decreasing 11 low abundance taxa, none of which are classical pulmonary pathogens. Compared with placebo, AZM treatment led to reduced in-vivo levels of chemokine (C-X-C) ligand 1 (CXCL1), tumour necrosis factor (TNF)-α, interleukin (IL)-13 and IL-12p40 in BAL, but increased bacterial metabolites including glycolic acid, indol-3-acetate and linoleic acid. Glycolic acid and indol-3-acetate, but not AZM, blunted ex-vivo LPS-induced alveolar macrophage generation of CXCL1, TNF-α, IL-13 and IL-12p40.. AZM treatment altered both lung microbiota and metabolome, affecting anti-inflammatory bacterial metabolites that may contribute to its therapeutic effects.. NCT02557958.

Topics: Aged; Anti-Bacterial Agents; Azithromycin; Bronchoalveolar Lavage Fluid; Chemokine CXCL1; Cytokines; Double-Blind Method; Female; Glycolates; Humans; Indoleacetic Acids; Inflammation; Interleukin-12 Subunit p40; Interleukin-13; Linoleic Acid; Lung; Macrophages, Alveolar; Male; Metabolome; Microbiota; Middle Aged; Pulmonary Emphysema; RNA, Ribosomal, 16S; Tumor Necrosis Factor-alpha

The study objectives were to refine the population pharmacokinetics (PK) model, determine microbial clearance, and assess short-term pulmonary outcomes of multiple-dose azithromycin treatment in preterm infants at risk for Ureaplasma respiratory colonization. Fifteen subjects (7 of whom were Ureaplasma positive) received intravenous azithromycin at 20 mg/kg of body weight every 24 h for 3 doses. Azithromycin concentrations were determined in plasma samples obtained up to 168 h post-first dose by using a validated liquid chromatography-tandem mass spectrometry method. Respiratory samples were obtained predose and at three time points post-last dose for Ureaplasma culture, PCR, antibiotic susceptibility testing, and cytokine concentration determinations. Pharmacokinetic data from these 15 subjects as well as 25 additional subjects (who received either a single 10-mg/kg dose [n = 12] or a single 20-mg/kg dose [n = 13]) were analyzed by using a nonlinear mixed-effect population modeling (NONMEM) approach. Pulmonary outcomes were assessed at 36 weeks post-menstrual age and 6 months adjusted age. A 2-compartment model with all PK parameters allometrically scaled on body weight best described the azithromycin pharmacokinetics in preterm neonates. The population pharmacokinetics parameter estimates for clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 0.15 liters/h · kg(0.75), 1.88 liters · kg, 1.79 liters/h · kg(0.75), and 13 liters · kg, respectively. The estimated area under the concentration-time curve over 24 h (AUC24)/MIC90 value was ∼ 4 h. All posttreatment cultures were negative, and there were no drug-related adverse events. One Ureaplasma-positive infant died at 4 months of age, but no survivors were hospitalized for respiratory etiologies during the first 6 months (adjusted age). Thus, a 3-day course of 20 mg/kg/day intravenous azithromycin shows preliminary efficacy in eradicating Ureaplasma spp. from the preterm respiratory tract.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Azithromycin; Bronchopulmonary Dysplasia; Cytokines; Humans; Infant; Infant, Newborn; Infant, Premature; Inflammation; Microbial Sensitivity Tests; Nonlinear Dynamics; Respiratory Tract Infections; Treatment Outcome; Ureaplasma; Ureaplasma Infections

Studies suggest that a single prophylactic dose of amoxicillin reduces early implant complications, but it is unclear whether other antibiotics are also effective. This study compared the local antimicrobial and anti-inflammatory effects resulting from a single dose of azithromycin or amoxicillin before surgical placement of one-stage dental implants.. Healthy adult patients requiring one-stage dental implant placement were allocated randomly to receive either 2 g amoxicillin (n = 7) or 500 mg azithromycin (n = 6) before surgery. Peri-implant crevicular fluid (PICF) samples from the new implant and gingival crevicular fluid (GCF) from adjacent teeth were sampled on postoperative days 6, 13, and 20. Inflammatory mediators in the samples were analyzed by immunoassay, and antibiotic levels were measured by bioassay.. On day 6, azithromycin concentrations in GCF and PICF were 3.39 ± 0.73 and 2.77 ± 0.90 μg/mL, respectively, whereas amoxicillin was below the limit of detection. During early healing, patents in the azithromycin group exhibited a significantly greater decrease in GCF volume (P = 0.03, analysis of variance). At specific times during healing, the azithromycin group exhibited significantly lower levels of interleukin (IL)-6 and IL-8 in GCF than the amoxicillin group and exhibited significantly lower levels of granulocyte colony stimulating factor, IL-8, macrophage inflammatory protein-1β, and interferon-gamma-inducible protein-10 in PICF.. Azithromycin was available at the surgical site for a longer period of time than amoxicillin, and patients taking azithromycin exhibited lower levels of specific proinflammatory cytokines and chemokines in GCF and PICF. Thus, preoperative azithromycin may enhance resolution of postoperative inflammation to a greater extent than amoxicillin.

Topics: Adult; Amoxicillin; Anti-Bacterial Agents; Azithromycin; Biological Availability; Dental Implants; Gingival Crevicular Fluid; Humans; Inflammation

We evaluated the efficacy of a 12-week oral treatment with azithromycin in adult patients with bronchiectasis. The objectives were to demonstrate that this treatment reduces sputum volume, improves quality of life and to assess the lengths of effects after cessation of therapy.. Seventy-eight patients with bronchiectasis confirmed by high-resolution computed tomography were included in this study. Subjects received oral azithromycin or placebo in a randomized manner for 12 weeks followed by placebo for another 12 weeks. Sputum volume, St George's Respiratory Questionnaire (SGRQ) score and spirometry were recorded at baseline, 12 weeks and 24 weeks, respectively. End-point measurements were compared from baseline to the end of each study phase.. Sixty-eight subjects were included in the analysis. Mean 24-h sputum volume significantly decreased (P < 0.01) during the active treatment phase and remained low during the control phase (P < 0.01). The mean SGRQ total score with azithromycin decreased (i.e. improved health status) from baseline by more than the 4 points at the end of 12 and 24 weeks. Lung functions remained stable during oral azithromycin therapy and the subsequent control phase.. Twelve weeks administration of azithromycin in bronchiectasis produces significant reductions in mean sputum volume, health status and stabilization of lung function values. Sputum volume reduction and the improvement of quality of life were sustained for 12 weeks after cessation of azithromycin. (Clinicaltrials.gov number NCT02107274).

Topics: Administration, Oral; Adult; Aged; Anti-Bacterial Agents; Azithromycin; Bronchiectasis; Drug Monitoring; Female; Health Status; Humans; Inflammation; Lung; Male; Middle Aged; Quality of Life; Respiratory Function Tests; Sputum; Treatment Outcome

Macrolide antibiotics have been shown beneficial in cystic fibrosis (CF) and diffuse panbronchiolitis, and earlier findings also suggest a benefit in non-CF bronchiectasis.. To determine the efficacy of macrolide maintenance treatment for adults with non-CF bronchiectasis.. The BAT (Bronchiectasis and Long-term Azithromycin Treatment) study, a randomized, double-blind, placebo-controlled trial conducted between April 2008 and September 2010 in 14 hospitals in The Netherlands among 83 outpatients with non-CF bronchiectasis and 3 or more lower respiratory tract infections in the preceding year.. Azithromycin (250 mg daily) or placebo for 12 months.. Number of infectious exacerbations during 12 months of treatment. Secondary end points included lung function, sputum bacteriology, inflammatory markers, adverse effects, symptom scores, and quality of life.. Forty-three participants (52%) received azithromycin and 40 (48%) received placebo and were included in the modified intention-to-treat analysis. At end of study, the median number of exacerbations in the azithromycin group was 0 (interquartile range [IQR], 0-1), compared with 2 (IQR, 1-3) in the placebo group (P < .001). Thirty-two (80%) placebo-treated vs 20 (46%) azithromycin-treated individuals had at least 1 exacerbation (hazard ratio, 0.29 [95% CI, 0.16-0.51]). In a mixed-model analysis, change in forced expiratory volume in the first second of expiration (percent of predicted) over time differed between groups (F1,78.8 = 4.085, P = .047), with an increase of 1.03% per 3 months in the azithromycin group and a decrease of 0.10% per 3 months in the placebo group. Gastrointestinal adverse effects occurred in 40% of patients in the azithromycin group and in 5% in the placebo group (relative risk, 7.44 [95% CI, 0.97-56.88] for abdominal pain and 8.36 [95% CI, 1.10-63.15] for diarrhea) but without need for discontinuation of study treatment. A macrolide resistance rate of 88% was noted in azithromycin-treated individuals, compared with 26% in the placebo group.. Among adults with non-CF bronchiectasis, the daily use of azithromycin for 12 months compared with placebo resulted in a lower rate of infectious exacerbations. This could result in better quality of life and might influence survival, although effects on antibiotic resistance need to be considered.. clinicaltrials.gov Identifier: NCT00415350.

Topics: Adult; Aged; Anti-Bacterial Agents; Azithromycin; Bacterial Infections; Biomarkers; Bronchiectasis; Double-Blind Method; Drug Resistance, Bacterial; Female; Humans; Inflammation; Lung; Male; Middle Aged; Quality of Life; Respiratory Function Tests; Respiratory Tract Infections; Sputum

Azithromycin reduces airway inflammation and improves forced expiratory volume in 1 s (FEV₁) in chronic rejection or bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). Azithromycin prophylaxis might prevent BOS. A double-blind randomised controlled trial of azithromycin (n = 40) or placebo (n = 43), initiated at discharge and administered three times a week for 2 yrs, was performed in 2005-2009 at the Leuven University Hospital (Leuven, Belgium). Primary end-points were BOS-free and overall survival 2 yrs after LTx; secondary end-points were acute rejection, lymphocytic bronchiolitis and pneumonitis rate, prevalence of pseudomonal airway colonisation or gastro-oesophageal reflux, and change in FEV₁, airway and systemic inflammation over time. Patients developing BOS were assessed for change in FEV₁ with open-label azithromycin. BOS occurred less in patients receiving azithromycin: 12.5 versus 44.2% (p = 0.0017). BOS-free survival was better with azithromycin (hazard ratio 0.27, 95% CI 0.092-0.816; p = 0.020). Overall survival, acute rejection, lymphocytic bronchiolitis, pneumonitis, colonisation and reflux were comparable between groups. Patients receiving azithromycin demonstrated better FEV₁ (p = 0.028), and lower airway neutrophilia (p = 0.015) and systemic C-reactive protein levels (p = 0.050) over time. Open-label azithromycin for BOS improved FEV₁ in 52.2% patients. No serious adverse events were noted. Azithromycin prophylaxis attenuates local and systemic inflammation, improves FEV₁ and reduces BOS 2 yrs after LTx.

Topics: Adult; Azithromycin; Bronchiolitis Obliterans; Disease-Free Survival; Double-Blind Method; Female; Forced Expiratory Volume; Graft Rejection; Humans; Immunosuppressive Agents; Inflammation; Lung Transplantation; Male; Middle Aged; Placebos; Proportional Hazards Models; Transplantation, Homologous; Treatment Outcome

Defective efferocytosis (phagocytic clearance of apoptotic cells) in the airway may perpetuate inflammation via secondary necrosis in chronic obstructive pulmonary disease (COPD). We have previously reported that low-dose azithromycin improved alveolar macrophage (AM) phagocytic function in vitro.. We investigated collectins (mannose-binding lectin [MBL] and surfactant protein [SP]-D) and mannose receptor (MR) in COPD and their possible role in the azithromycin-mediated improvement in phagocytosis.. In vitro effects of azithromycin on AM expression of MR were investigated. MBL, SP-D, and MR were measured in patients with COPD and control subjects. Azithromycin (250 mg orally daily for 5 d then twice weekly for 12 wk) was administered to 11 patients with COPD. Assessments included AM phagocytic ability and expression of MR, MBL, SP-D, bronchial epithelial cell apoptosis, pulmonary function, C-reactive protein, blood/BAL leukocyte counts, cytokine production, and T-cell markers of activation and phenotype.. Azithomycin (500 ng/ml) increased MR expression by 50% in vitro. AM MR expression and levels of MBL and SP-D were significantly reduced in patients with COPD compared with control subjects. In patients with COPD, after azithromycin therapy, we observed significantly improved AM phagocytic ability (pre: 9.9%; post: 15.1%), reduced bronchial epithelial cell apoptosis (pre: 30.0%; post: 19.7%), and increased MR and reduced inflammatory markers in the peripheral blood. These findings implicate the MR in the defective phagocytic function of AMs in COPD and as a target for the azithromycin-mediated improvement in phagocytic ability.. Our findings indicate a novel approach to supplement existing therapies in COPD.

Topics: Adult; Aged; Anti-Bacterial Agents; Apoptosis; Azithromycin; Bronchoalveolar Lavage Fluid; Case-Control Studies; Cells, Cultured; Collectins; Female; Humans; Inflammation; Lectins, C-Type; Macrophages, Alveolar; Male; Mannose Receptor; Mannose-Binding Lectins; Middle Aged; Phagocytosis; Pulmonary Disease, Chronic Obstructive; Receptors, Cell Surface; Respiratory Mucosa; Statistics, Nonparametric

The anti-inflammatory potential of azithromycin in chronic obstructive pulmonary disease (COPD) patients was explored following a standard oral dosing regimen. Patients with moderate and severe COPD were treated with azithromycin (500 mg, n=16) or placebo (n=8) once daily for 3 days in a randomized, double blind design, to compare effects on inflammation markers with those seen in a previous study in healthy volunteers. A battery of tests was made on serum, blood neutrophils and sputum on days 1 (baseline), 3, 4, 11, 18 and 32. In comparison to placebo, azithromycin resulted in an early transient increase in serum nitrites plus nitrates (day 3), associated with a tendency towards an increase in the blood neutrophil oxidative burst to phorbol myristic acetate. Subsequently, prolonged decreases in blood leukocyte and platelet counts, serum acute phase protein (including C reactive protein) and soluble E-selectin and blood neutrophil lactoferrin concentrations and a transient decrease in serum interleukin-8 were observed. Blood neutrophil glutathione peroxidase activity showed a prolonged increase after azithromycin treatment. The biphasic facilitatory-then-inhibitory response to azithromycin seen in healthy volunteers is not so clearly detectable in COPD patients, only potential anti-inflammatory effects. Treatment for longer periods may give therapeutic anti-inflammatory benefit in these patients.

Topics: Adult; Aged; Anti-Inflammatory Agents; Azithromycin; Biomarkers; Blood Cell Count; C-Reactive Protein; Cell Count; Double-Blind Method; E-Selectin; Glutathione; Glutathione Peroxidase; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocytes; Humans; Inflammation; Interleukin-6; Interleukin-8; Lactoferrin; Male; Middle Aged; Neutrophils; Nitrates; Nitrites; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Respiratory Burst; Respiratory Function Tests; Serum Amyloid A Protein; Sputum; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Infection with Helicobacter pylori and Chlamydia pneumoniae is associated with coronary heart disease. We conducted an intervention study using antibiotics against these bacteria in patients with acute coronary syndromes to determine whether antibiotics reduce inflammatory markers and adverse cardiac events.. Patients (n=325) admitted with acute myocardial infarction or unstable angina (acute coronary syndromes) were randomized to receive a 1-week course of 1 of 3 treatment regimens: (1) placebo; (2) amoxicillin (500 mg twice daily), metronidazole (400 mg twice daily), and omeprazole (20 mg twice daily); or (3) azithromycin (500 mg once daily), metronidazole (400 mg twice daily), and omeprazole (20 mg twice daily). Serum fibrinogen, white cell count, and high-sensitivity C-reactive protein were measured at study entry and at 1, 3, and 12 months during follow-up. Cardiac death and readmission with acute coronary syndrome were considered clinical end points. Patients were followed for 1 year. C-reactive protein levels were reduced (P=0.03) in unstable angina patients receiving amoxicillin, and fibrinogen was reduced in both patient groups receiving antibiotics (P=0.06). There were 17 cardiac deaths and 71 readmissions with acute coronary syndrome. No difference in frequency or timing of end points was observed between the 2 antibiotic groups. At 12 weeks, there was a 36% reduction in all end points in patients receiving antibiotics compared with placebo (P=0.02). This reduction persisted during the 1-year follow-up. Neither C pneumoniae nor H pylori antibody status was significantly related to response to treatment.. Antibiotic treatment significantly reduced adverse cardiac events in patients with acute coronary syndromes, but the effect was independent of H pylori or C pneumoniae seropositivity.

Topics: Acute Disease; Adolescent; Adult; Aged; Amoxicillin; Angina, Unstable; Anti-Bacterial Agents; Antibodies, Bacterial; Azithromycin; Biomarkers; Chlamydophila Infections; Chlamydophila pneumoniae; Disease-Free Survival; Double-Blind Method; Female; Helicobacter Infections; Helicobacter pylori; Humans; Inflammation; Male; Middle Aged; Myocardial Infarction; Syndrome

Topics: Ampicillin; Azithromycin; Genital Diseases, Male; Humans; Inflammation; Male; Urinary Tract Infections

We evaluated the clinical features of postoperative anterior blepharitis following cataract surgery and the efficacy of topical azithromycin retrospectively. Thirty eyes of 30 patients with a clinical diagnosis of anterior blepharitis by 6 months postoperatively among those who underwent cataract surgery at our institution between November 2020 and June 2022 were included. The diagnosis of anterior blepharitis and the assessment of objective and subjective findings were based on the American Academy of Ophthalmology Blepharitis Preferred Practice Pattern

Topics: Anti-Bacterial Agents; Azithromycin; Blepharitis; Cataract; Eye Diseases; Foreign Bodies; Humans; Inflammation; Meibomian Gland Dysfunction; Ophthalmic Solutions; Retrospective Studies

Long term macrolide treatment has been found beneficial in bronchiectasis (BE) -pathogical bronchial dilatation- possibly due to a combined anti-bacterial and immunomodulatory effect. The exact mechanism of inflammatory response is unknown. Here, we investigated the effect of maintenance macrolide treatment on the inflammatory response in BE. In addition, we assessed the inflammatory profile in BE in relation to disease severity.. During the BAT randomized controlled trial (investigating the effect of 1 year of azithromycin (AZM) in 83 BE patients), data on BE severity, lung function and sputum microbiology was collected. For the current study, a wide range of inflammatory markers were analysed in 3- monthly sputum samples in all participants.. At baseline, marked neutrophilic but also eosinophilic inflammation was present in both groups, which remained stable throughout the study and was not affected by AZM treatment. Significant upregulation of pro-inflammatory markers correlated with FEV. One year of AZM treatment did not result in attenuation of the inflammatory response in BE. Increasing disease severity and the presence of an exacerbation were reflected by upregulation of pro-inflammatory markers.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchi; Bronchiectasis; Humans; Inflammation; Interleukin-1; Macrolides; Sputum; Tumor Necrosis Factor-alpha

Previous in vitro transcriptomic profiling suggests azithromycin exerts its effects in patients with chronic rhinosinusitis (CRS) via modulation of type 1 inflammation and restoration of epithelial barrier function. We wished to verify these postulated effects using in vitro models of epithelial repair and in vivo transcriptional profiling.. Functional effects of azithromycin in CRS were verified using in vitro models of wounding. The mechanism of the effect of azithromycin was assessed in vivo using transcriptomic profiling.. Academic medical center.. Effects of azithromycin on the speed of epithelial repair were verified in a wounding model using primary nasal epithelial cells (pNEC) from CRS patients. Nasal brushings collected pre-and posttreatment during a placebo-controlled trial of azithromycin for CRS patients unresponsive to surgery underwent transcriptomic profiling to identify implicated pathways.. Administration of azithromycin improved the wound healing rates in CRS pNECs and prevented the negative effect of Staphylococcus aureus on epithelial repair. In vivo, response to azithromycin was associated with downregulation in pathways of type 1 inflammation, and upregulation of pathways implicated in the restoration of the cell cycle.. Restoration of healthy epithelial function may represent a major mode of action of azithromycin in CRS. In vitro models show enhanced epithelial repair, while in vivo transcriptomics shows downregulation of pathways type 1 inflammation accompanied by upregulation of DNA repair and cell-cycle pathways. The maximal effect in patients with high levels of type 1-enhanced inflammation suggests that azithromycin may represent a novel therapeutic option for surgery-unresponsive CRS patients.

Topics: Azithromycin; Chronic Disease; Humans; Inflammation; Nasal Mucosa; Nasal Polyps; Rhinitis; Sinusitis

To evaluate the efficacy of azithromycin hydrate ophthalmic solution for the treatment of internal hordeolum and meibomitis with or without phlyctenular keratitis.. Retrospective study.. Patients diagnosed with internal hordeolum or meibomitis were prescribed azithromycin hydrate ophthalmic solution twice daily for 2 days and then once daily for 12 days. Depending on the presence of meibomitis-related keratoconjunctivitis (MRKC), we further divided the patients with meibomitis into three subgroups: meibomitis alone (non-MRKC group), meibomitis with non-phlyctenular MRKC (non-phlyctenular group), and meibomitis with phlyctenular MRKC (phlyctenular group). Inflammatory findings (eyelid redness and conjunctival hyperemia) were scored before and after treatment. Some patients also underwent culture testing fluids discharged by the meibomian gland orifices.. Three patients (3 eyes) had internal hordeolum and 16 patients (16 eyes) had meibomitis. After treatment, the inflammatory findings disappeared in all eyes with internal hordeolum. Among the patients with meibomitis, three eyes were in the non-MRKC, six in the non-phlyctenular, and seven in the phlyctenular group. The inflammatory findings were significantly improved only in the phlyctenular group. Among seven eyes with positive culture results, Cutibacterium acnes was detected in five, and treatment improved the inflammatory findings in all of these eyes.. Azithromycin hydrate ophthalmic solution is effective for the treatment of inflammatory meibomian gland diseases, including internal hordeolum and meibomitis. In particular, the agent is highly efficient in patients with phlyctenular MRKC.

Topics: Anti-Bacterial Agents; Azithromycin; Blepharitis; Hordeolum; Humans; Inflammation; Keratitis; Keratoconjunctivitis; Meibomian Glands; Meibomitis; Ophthalmic Solutions; Retrospective Studies

Primary ciliary dyskinesia (PCD) is a genetic disorder associated with recurrent and chronic respiratory infections due to functional defects of motile cilia. In this study, we aimed to elucidate inflammatory and proliferative responses in PCD respiratory epithelium and evaluate the effect of Azithromycin (AZT) on these responses. Airway basal cells (BCs) were isolated from nasal samples of Wild-type (WT) epitope of healthy donors and PCD donors with bi-allelic mutations in DNAH5, DNAH11 and CCDC39. Cells were expanded in vitro and stimulated with either Lipopolysaccharide (LPS) or vehicle control. Post stimulation, cells were treated with either Azithromycin (AZT) or vehicle control. Cell proliferation was imaged in real-time. Separately, BCs from the same donors were expanded and grown at an air-liquid interface (ALI) to generate a multi-ciliated epithelium (MCE). Once fully mature, cells were stimulated with LPS, AZT, LPS + AZT or vehicle control. Inflammatory profiling was performed on collected media by cytokine Luminex assay. At baseline, there was a significantly higher mean production of pro-inflammatory cytokines by CCDC39 BCs and MCEs when compared to WT, DNAH11 and DNAH5 cells. AZT inhibited production of cytokines induced by LPS in PCD cells. Differences in cell proliferation were noted in PCD and this was also corrected with AZT treatment.

Topics: Azithromycin; Cell Proliferation; Ciliary Motility Disorders; Cytokines; Epithelial Cells; Humans; Inflammation; Lipopolysaccharides

Bacterial infection causes lung inflammation and recruitment of several inflammatory factors that may result in acute lung injury (ALI). During bacterial infection, reactive oxygen species (ROS) and other signaling pathways are activated, which intensify inflammation and increase ALI-related mortality and morbidity. To improve the ALI therapy outcome, it is imperative clinically to manage bacterial infection and excessive inflammation simultaneously. Herein, a synergistic nanoplatform (AZI+IBF@NPs) constituted of ROS-responsive polymers (PFTU), and antibiotic (azithromycin, AZI) and anti-inflammatory drug (ibuprofen, IBF) was developed to enable an antioxidative effect, eliminate bacteria, and modulate the inflammatory milieu in ALI. The ROS-responsive NPs (PFTU NPs) loaded with dual-drugs (AZI and IBF) scavenged excessive ROS efficiently both in vitro and in vivo. The AZI+IBF@NPs eradicated Pseudomonas aeruginosa (PA) bacterial strain successfully. To imitate the entry of bacterial-derived compounds in body, a lipopolysaccharide (LPS) model was adopted. The administration of AZI+IBF@NPs via the tail veins dramatically reduced the number of neutrophils, significantly reduced cell apoptosis and total protein concentration in vivo. Furthermore, nucleotide oligomerization domain-like receptor thermal protein domain associated protein 3 (NLRP3) and Interleukin-1 beta (IL-1β) expressions were most effectively inhibited by the AZI+IBF@NPs. These findings present a novel nanoplatform for the effective treatment of ALI.

Topics: Acute Lung Injury; Azithromycin; Bacterial Infections; Humans; Ibuprofen; Inflammation; Nanoparticles; Polymers; Reactive Oxygen Species

Systemic inflammation amplifies neonatal hypoxic-ischemic (HI) brain injury. Azithromycin (AZ), an antibiotic with anti-inflammatory properties, improves sensorimotor function and reduces tissue damage after neonatal rat HI brain injury. The objective of this study was to determine if AZ is neuroprotective in two neonatal rat models of inflammation-amplified HI brain injury.. Seven-day-old (P7) rats received injections of toll-like receptor agonists lipopolysaccharide (LPS) or Pam. In both LPS + HI and PAM + HI models, AZ improved sensorimotor function, survival, brain tissue preservation, and composite scores. Benefits increased with five- vs. three-dose AZ and declined with longer initiation delay.. Perinatal systemic infection is a common comorbidity of neonatal asphyxia brain injury and contributes to adverse outcomes. These data support further evaluation of AZ as a candidate treatment for neonatal neuroprotection.. AZ treatment decreases sensorimotor impairment and severity of brain injury, and improves survival, after inflammation-amplified HI brain injury, and this can be achieved even with a 2 h delay in initiation. This neuroprotective benefit is seen in models of inflammation priming by both Gram-negative and Gram-positive infections. This extends our previous findings that AZ treatment is neuroprotective after HI brain injury in neonatal rats.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Brain; Brain Injuries; Hypoxia-Ischemia, Brain; Inflammation; Lipopolysaccharides; Neuroprotective Agents; Oxygen; Rats; Rats, Wistar; Toll-Like Receptors

The World Health Organization recommends mass drug administration (MDA) with azithromycin to eliminate trachoma as a public health problem. MDA decisions are based on prevalence estimates from two-stage cluster surveys. There is a need to mathematically evaluate current trachoma survey designs. Our study aimed to characterize the effects of the number of units sampled on the precision and cost of trachomatous inflammation-follicular (TF) estimates.. A population of 30 districts was simulated to represent the breadth of possible TF distributions in Amhara, Ethiopia. Samples of varying numbers of clusters (14-34) and households (10-60) were selected. Sampling schemes were evaluated based on precision, proportion of incorrect and low MDA decisions made, and estimated cost.. The number of clusters sampled had a greater impact on precision than the number of households. The most efficient scheme depended on the underlying TF prevalence in a district. For lower prevalence areas (< 10%) the most cost-efficient design (providing adequate precision while minimizing cost) was 20 clusters of 20-30 households. For higher prevalence areas (> 10%), the most efficient design was 15-20 clusters of 20-30 households.. For longer-running programs, using context-specific survey designs would allow for practical precision while reducing survey costs. Sampling 15 clusters of 20-30 households in suspected moderate-to-high prevalence districts and 20 clusters of 20-30 households in districts suspected to be near the 5% threshold appears to be a balanced approach.

Topics: Azithromycin; Ethiopia; Humans; Infant; Inflammation; Prevalence; Trachoma

Inflammatory diseases including COVID-19 are associated with a cytokine storm characterized by high interleukin-6 (IL-6) titers. In particular, while recent studies examined COVID-19 associated arrhythmic risks from cardiac injury and/or from pharmacotherapy such as the combination of azithromycin (AZM) and hydroxychloroquine (HCQ), the role of IL-6 per se in increasing the arrhythmic risk remains poorly understood. The objective is to elucidate the electrophysiological basis of inflammation-associated arrhythmic risk in the presence of AZM and HCQ. IL-6, AZM and HCQ were concomitantly administered to guinea pigs in-vivo and in-vitro. Electrocardiograms, action potentials and ion-currents were analyzed. IL-6 alone or the combination AZM + HCQ induced mild to moderate reduction in heart rate, PR-interval and corrected QT (QTc) in-vivo and in-vitro. Notably, IL-6 alone was more potent than the combination of the two drugs in reducing heart rate, increasing PR-interval and QTc. In addition, the in-vivo or in-vitro combination of IL-6 + AZM + HCQ caused severe bradycardia, conduction abnormalities, QTc prolongation and asystole. These electrocardiographic abnormalities were attenuated in-vivo by tocilizumab (TCZ), a monoclonal antibody against IL-6 receptor, and are due in part to the prolongation of action potential duration and selective inhibition of Na

Topics: Animals; Antibodies, Monoclonal, Humanized; Arrhythmias, Cardiac; Azithromycin; COVID-19; COVID-19 Drug Treatment; Female; Guinea Pigs; Humans; Hydroxychloroquine; Inflammation; Interleukin-6; Male; SARS-CoV-2

Excessive production, secretion, and retention of abnormal mucus is a pathological feature of many obstructive airways diseases including asthma. Azithromycin is an antibiotic that also possesses immunomodulatory and mucoregulatory activities, which may contribute to the clinical effectiveness of azithromycin in asthma. The current study investigated these nonantibiotic activities of azithromycin in mice exposed daily to intranasal house dust mite (HDM) extract for 10 days. HDM-exposed mice exhibited airways hyperresponsiveness to aerosolized methacholine, a pronounced mixed eosinophilic and neutrophilic inflammatory response, increased airway smooth muscle (ASM) thickness, and elevated levels of epithelial mucin staining. Azithromycin (50 mg/kg sc, 2 h before each HDM exposure) attenuated HDM-induced airways hyperresponsiveness to methacholine, airways inflammation (bronchoalveolar lavage eosinophil and neutrophils numbers, and IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, and RANTES levels), and epithelial mucin staining (mucous metaplasia) by at least 50% (compared with HDM-exposed mice,

Topics: Adenosine Triphosphate; Allergens; Animals; Asthma; Azithromycin; Disease Models, Animal; Inflammation; Interleukin-13; Metaplasia; Methacholine Chloride; Mice; Mucins; Mucus; Pyroglyphidae

Asthma is a respiratory disease; involving millions of people worldwide. The main cause of asthma is allergy and immune response dysregulation. The effects of azithromycin and doxycycline as asthma-controlling drugs were evaluated in this study. Mice asthma model was produced and asthmatic mice were treated with azithromycin (75 mg/kg, orally) and doxycycline (20 mg/kg, orally). Eosinophils and neutrophils count, interleukin (IL)-4, IL-5, IL-12, IL-13, and total immunoglobulin E (IgE) levels were measured. Histological study and evaluating the genes expression of Muc5ac, Muc5b, IL-33, COX2, MYD88, and TRAF6 were performed. Azithromycin and doxycycline did not affect eosinophil and neutrophil percentage, IL-4, IL-5, IL-12, and total IgE levels, peribronchial and perivascular inflammation, goblet cell hyperplasia, and gene expression of MYD88, TRAF6, and COX2. Treatment with azithromycin significantly decreased IL-13 level, mucus secretion, and gene expression of IL-33, Muc5ac, and Muc5b; compared to the non-treated asthma group. Azithromycin administration controls mucus secretion and inflammation. Azithromycin therapy and not doxycycline might be an effective adjuvant option in asthma with reducing mucus in the airway.

Topics: Animals; Asthma; Azithromycin; Cyclooxygenase 2; Doxycycline; Humans; Immunoglobulin E; Inflammation; Interleukin-12; Interleukin-13; Interleukin-33; Interleukin-5; Mice; Mucus; Myeloid Differentiation Factor 88; Signal Transduction; TNF Receptor-Associated Factor 6

Antibiotic resistance is a major problem, with methicillin-resistant Staphylococcus aureus (MRSA) being a prototypical example in surgical and community-acquired infections. S. aureus, like many pathogens, is immune evasive and able to multiply within host immune cells. Consequently, compounds that aid host immunity (e.g., by stimulating the host-mediated killing of pathogens) are appealing alternatives or adjuncts to classical antibiotics. Azithromycin is both an antibacterial and an immunomodulatory drug that accumulates in immune cells. We set out to improve the immunomodulatory properties of azithromycin by coupling the immune activators, nitric oxide and acetate, to its core structure. This new compound, designated CSY5669, enhanced the intracellular killing of MRSA by 45% ± 20% in monocyte-derived macrophages and by 55% ± 15% in peripheral blood leukocytes, compared with untreated controls. CSY5669-treated peripheral blood leukocytes produced fewer proinflammatory cytokines, while in both monocyte-derived macrophages and peripheral blood leukocytes, phagocytosis, ROS production, and degranulation were unaffected. In mice with MRSA pneumonia, CSY5669 treatment reduced inflammation, lung pathology and vascular leakage with doses as low as 0.01 μmol/kg p.o. CSY5669 had diminished direct

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Cytokines; Inflammation; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Nitric Oxide; Pneumonia, Staphylococcal; Prodrugs; Reactive Oxygen Species; Staphylococcal Infections; Staphylococcus aureus

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

Uveitis is one of the most common blindness-causing ocular disorders. Due to its complicated pathogenesis, the treatment of uveitis has been widely recognized as a challenge for ophthalmologists. Recently, the anti-inflammatory properties of the antibiotic Azithromycin (AZM) have been reported. However, the therapeutic effects of Azithromycin in experimental autoimmune uveitis (EAU), a representative model of human AU, have not been elucidated till date. We conducted this study to examine the therapeutic effects and potential mechanisms of Azithromycin in EAU. We observed that Azithromycin significantly attenuated retinal inflammation in EAU mice at day 14 after immunization along with a significantly decreased inflammatory cell infiltration and cytokine production in the retina. Furthermore, we observed that Azithromycin increased the number of regulatory T cells (Treg) and decreased the number of effector T cells (Teff) in both the draining lymph nodes and spleen of EAU mice. Additionally, Azithromycin suppressed the proliferation and activation of CD4 + T cells, and induced the apoptosis of CD4 + CD44 + memory T and CD4 + CXCR3 + Th1 cells. Mechanistically, we proved that Azithromycin could regulate Teff/Treg balance by inhibiting the phosphorylation of S6 ribosomal protein, a downstream target of mammalian target of rapamycin (mTOR). Together, our findings revealed that Azithromycin alleviated EAU by regulating the Teff/Treg balance through the mTOR signaling pathway, suggesting that Azithromycin could be a promising therapeutic candidate for AU.

Topics: Adoptive Transfer; Animals; Anti-Bacterial Agents; Apoptosis; Azithromycin; Cell Proliferation; Female; Gene Expression Regulation; Inflammation; Mice; Mice, Inbred C57BL; Peptide Fragments; Retinal Diseases; Retinol-Binding Proteins; T-Lymphocyte Subsets; TOR Serine-Threonine Kinases; Transcriptome

Mycobacterium abscessus complex (MABC) infections cause significant morbidity and mortality among patients with chronic lung disease, like cystic fibrosis. MABC exists in smooth (S) and rough (R) morphotypes, but triggers of morphotype switching and associated pathogenicity or antimicrobial susceptibility are poorly understood. We demonstrate that M. abscessus subspecies abscessus (Mab), massiliense (Mms), and bolletii (Mbl) cultured in Middlebrook (MB) broth exhibit S morphotype, whereas the bacteria grown in Luria Bertani (LB) broth adopt the R morphotype, characterized by low glycopeptidolipid (GPL) expression. The components of broth that mediate this selection are complex, with albumin supplementation promoting growth of S morphotype, but not sufficient for complete selection. Consistent with the findings of other groups, R forms of Mab, Mms and Mbl selected by LB broth were internalized in RAW 264.7 macrophages with higher efficiency than S. Intracellular survival of broth-selected organisms was variable and was higher for S Mab, but lower for S Mms and Mbl. It is proposed that growth in R morphotype is induced during stress conditions, such as nutrient poor environments or during inflammation. One key component of inflammation is release of nitric oxide. We demonstrated that a nitric oxide donor (DETA-NONOate) appears to induce growth in an R morphotype, as indicated by reduced GPL expression of Mab. Mab treated with DETA-NONOate also enhanced susceptibility to azithromycin at sub-MIC concentrations. In conclusion, morphotype and macrophage intracellular bacterial load of MABC subspecies can be manipulated by growing the bacteria in different culture conditions. Nitric oxide may also drive morphotype selection and enhanced azithromycin activity against Mab and macrophage killing.

Topics: Azithromycin; Culture Media, Conditioned; Drug Resistance, Bacterial; Humans; Inflammation; Mycobacterium abscessus; Nitric Oxide; Virulence

More than 17 million people in the US provide uncompensated care for adults with physical or cognitive limitations. Such caregiving is associated with worse mental and physical health, yet little research has investigated how publicly funded home care might ameliorate these harms.. To investigate the association between Medicaid home care services and family caregivers' health.. This longitudinal cohort study used data from the 1996 to 2017 Medical Expenditures Panel Survey. Data on all household members were collected in 5 interviews over 2 years. Person-level difference-in-difference models were used to isolate within-person changes associated with new onset of Medicaid home care. The Medical Expenditures Panel Survey longitudinal data sets included 331 202 individuals (approximately 10% excluded owing to loss to follow-up). Adult (age ≥21 years) members of households that contained at least 1 person with limited activities of daily living were included in our study. The analysis itself was performed from March to August of 2020.. New onset of regular (≥1 time per month) Medicaid home care in the household.. Self-rated mental and physical health (planned prior to beginning the study).. In this cohort study, Medicaid home care was associated with improvement in caregiver self-rated mental health, but not with any short-term change in self-rated physical health. When evaluating the social value of home care programs, policy makers should consider spillover benefits to caregivers.. For all treatment-naïve patients, TBR

Topics: Activities of Daily Living; Adult; Air Pollution, Indoor; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antioxidants; Azithromycin; Canada; Carbon; Caregivers; Chlorine; Cohort Studies; Corn Oil; COVID-19 Drug Treatment; Daphnia; Dust; Ecosystem; Electrodes; Environmental Monitoring; Fatty Acids; Female; Flavonoids; Fluorides; Glycosides; Greece; Groundwater; Hippocampus; Home Care Services; Humans; Infant; Inflammation; Iridoids; Lamiaceae; Longitudinal Studies; Male; Medicaid; Memory; Metals, Heavy; Methanol; Mice; Microplastics; Middle Aged; N-Methylaspartate; Neural Networks, Computer; Nitrates; Nitrogen Oxides; Nylons; Obesity; Oleic Acid; Olive Oil; Oxidation-Reduction; Phosphorus; Place Cells; Plant Components, Aerial; Plant Extracts; Plastics; Polyesters; Polyurethanes; Prevalence; Quinic Acid; Reactive Oxygen Species; Receptors, N-Methyl-D-Aspartate; Risk Assessment; Sodium Chloride; Soil; Soil Pollutants; Stachys; Staphylococcus aureus; Stearic Acids; Superoxide Dismutase; U937 Cells; United States; Water; Water Pollutants, Chemical; Young Adult

Azithromycin is widely used broad spectrum antibiotic recently used in treatment protocol of COVID-19 for its antiviral and immunomodulatory effects combined with Hydroxychloroquine or alone. Rat models showed that Azithromycin produces oxidative stress, inflammation, and apoptosis of myocardial tissue. Rosuvastatin, a synthetic statin, can attenuate myocardial ischemia with antioxidant and antiapoptotic effects. This study aims to evaluate the probable protective effect of Rosuvastatin against Azithromycin induced cardiotoxicity.. Twenty adult male albino rats were divided randomly into four groups, five rats each control, Azithromycin, Rosuvastatin, and Azithromycin +Rosuvastatin groups. Azithromycin 30 mg/kg/day and Rosuvastatin 2 mg/kg/day were administrated for two weeks by an intragastric tube. Twenty-four hours after the last dose, rats were anesthetized and the following measures were carried out; Electrocardiogram, Blood samples for Biochemical analysis of lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). The animals sacrificed, hearts excised, apical part processed for H&E, immunohistochemical staining, and examined by light microscope. The remaining parts of the heart were collected for assessment of Malondialdehyde (MDA) and Reduced Glutathione (GSH).. The results revealed that Rosuvastatin significantly ameliorates ECG changes, biochemical, and Oxidative stress markers alterations of Azithromycin. Histological evaluation from Azithromycin group showed marked areas of degeneration, myofibers disorganization, inflammatory infiltrate, and hemorrhage. Immunohistochemical evaluation showed significant increase in both Caspase 3 and Tumor necrosis factor (TNF) immune stain. Rosuvastatin treated group showed restoration of the cardiac muscle fibers in H&E and Immunohistochemical results.. We concluded that Rosuvastatin significantly ameliorates the toxic changes of Azithromycin on the heart.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Apoptosis; Azithromycin; Cardiotoxicity; COVID-19 Drug Treatment; Disease Models, Animal; Glutathione; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Sprague-Dawley; Rosuvastatin Calcium

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening lung disease characterized by the proliferation of myofibroblasts and deposition of extracellular matrix that results in irreversible distortion of the lung structure and the formation of focal fibrosis. The molecular mechanism of IPF is not fully understood, and there is no satisfactory treatment. However, most studies suggest that abnormal activation of transforming growth factor-β1 (TGF-β1) can promote fibroblast activation and epithelial to mesenchymal transition (EMT) to induce pulmonary fibrosis. Deglycosylated azithromycin (Deg-AZM) is a compound we previously obtained by removing glycosyls from azithromycin; it was demonstrated to exert little or no antibacterial effects. Here, we discovered a new function of Deg-AZM in pulmonary fibrosis.

Topics: Animals; Azithromycin; Bleomycin; Cell Movement; Cell Proliferation; Epithelial Cells; Epithelial-Mesenchymal Transition; Glycosylation; Idiopathic Pulmonary Fibrosis; Inflammation; Lung; Mice; Models, Biological; Myofibroblasts; NIH 3T3 Cells; Oxidative Stress; Phenotype; Signal Transduction; Transforming Growth Factor beta1

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Age Factors; Angiotensin-Converting Enzyme Inhibitors; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Antiviral Agents; Azithromycin; Bromhexine; Coronavirus Infections; COVID-19; Cytokines; Expectorants; Humans; Hydroxychloroquine; Hypertension; Inflammation; Interferon beta-1a; Interleukin-1; Interleukin-12; Interleukin-6; Lymphohistiocytosis, Hemophagocytic; Obesity; Pandemics; Pneumonia, Viral; Pulmonary Disease, Chronic Obstructive; Respiratory Distress Syndrome; Risk Factors; Smoking; Tumor Necrosis Factor-alpha

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Betacoronavirus; Ceftriaxone; Coronavirus Infections; COVID-19; Diagnosis, Differential; Erythema Multiforme; Humans; Inflammation; Male; Pandemics; Pneumonia, Viral; SARS-CoV-2; Tomography, X-Ray Computed; Treatment Outcome

The purpose of the present study was to compare the immunomodulatory effect of azithromycin (AZM), ampicillin (AMP), amoxicillin (AMX), and clindamycin (CLI) in vitro and AZM on preexisting periapical lesions compared with AMP.. The susceptibility of 4 common human endodontic pathogens (Parvimonas micra, Streptococcus intermedius, Prevotella intermedia, and Fusobacterium nucleatum) to AZM, AMP, AMX, and CLI was confirmed by agar disk diffusion assay. Preexisting periapical lesions in C57BL/6J mice were treated with AZM, AMP, or phosphate-buffered saline (PBS). Periapical bone healing and the pattern of inflammatory cell infiltration were evaluated after a 10-day treatment by micro-computed tomographic and histology, respectively. Besides, the effect of antibiotics in pathogen-stimulated nuclear factor kappa B activation and the production of interleukin 1 alpha and tumor necrosis factor alpha was assessed in vitro by luciferase assay and enzyme-linked immunosorbent assay.. All examined endodontic pathogens were susceptible to AZM, AMP, AMX, and CLI. AZM significantly attenuated periapical bone loss versus PBS. PBS resulted in widely diffused infiltration of mixed inflammatory cells. By contrast, AZM brought about localized infiltration of neutrophils and M2 macrophages and advanced fibrosis. Although the effect of AMP on bone was uncertain, inflammatory cell infiltration was considerably milder than PBS. However, most macrophages observed seemed to be M1 macrophages. AZM suppressed pathogen-stimulated nuclear factor kappa B activation and cytokine production, whereas AMP, AMX, and CLI reduced only cytokine production moderately.. This study showed that AZM led to the resolution of preexisting experimental periapical inflammation. Our data provide a perspective on host response in antibiotic selection for endodontic treatment. However, well-designed clinical trials are necessary to better elucidate the benefits of AZM as an adjunctive therapy for endodontic treatment when antibiotic therapy is recommended. Although both AZM and AMP were effective on preexisting periapical lesions, AZM led to advanced wound healing, probably depending on its immunomodulatory effect.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Firmicutes; Immunomodulation; Inflammation; Mice; Mice, Inbred C57BL

COVID-19 is characterized by fast deterioration in the mechanism of cytokine storm. Therefore, treatment with immunomodulating agents should be initiated as soon as hyperinflammation is established. Evidence for the use of tocilizumab (TCZ) in COVID-19 is emerging, but the drug in this setting is used "off label" with limited data on both effectiveness and safety. Therefore, Hospital for Infectious Diseases in Warsaw established a Standard Operating Procedure (SOP) for the use of TCZ in severe COVID-19 cases.. Here, we present a case of 27-year-old, otherwise healthy man, who was successfully treated with chloroquine, azithromycin, tocilizumab and a standard of care. Initially the magnitude of lung devastation, clinical deterioration and the need for mechanical ventilation suggested unfavorable prognosis. However, we observed complete regression in radiological changes and rapid clinical improvement. Irrespective of this, patient's serum interleukin 6 and aminotransferases remained elevated even after a month from treatment.. An overlapping effect of hyperinflammation, hypoxic organ injury and drug-related toxicity warrants a long-term follow-up for COVID-19 survivors. In addition, residual IL-6 receptors blockage may mask new infections. A standardized approach to follow-up for COVID-19 survivors is urgently needed. Current and future research should also investigate the impact of experimental therapies on lung tissue healing and regeneration, as well as long-term treatment toxicities.

Topics: Adult; Antibodies, Monoclonal, Humanized; Azithromycin; Betacoronavirus; Chloroquine; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cytokines; Humans; Inflammation; Male; Off-Label Use; Pandemics; Pneumonia, Viral; Poland; SARS-CoV-2; Tomography, X-Ray Computed

Azithromycin (AZM) and other macrolide antibiotics are applied as immunomodulatory treatments for CNS disorders. The immunomodulatory and antibiotic properties of AZM are purportedly independent.. To improve the efficacy and reduce antibiotic resistance risk of AZM-based therapies, we evaluated the immunomodulatory and neuroprotective properties of novel AZM derivatives. We semisynthetically prepared derivatives by altering sugar moieties established as important for inhibiting bacterial protein synthesis. Bone marrow-derived macrophages (BMDMs) were stimulated in vitro with proinflammatory, M1, stimuli (LPS + INF-gamma) with and without derivative costimulation. Pro- and anti-inflammatory cytokine production, IL-12 and IL-10, respectively, was quantified using ELISA. Neuron culture treatment with BMDM supernatant was used to assess derivative neuroprotective potential.. Azithromycin and some derivatives increased IL-10 and reduced IL-12 production of M1 macrophages. IL-10/IL-12 cytokine shifts closely correlated with the ability of AZM and derivatives to mitigate macrophage neurotoxicity.. Sugar moieties that bind bacterial ribosomal complexes can be modified in a manner that retains AZM immunomodulation and neuroprotection. Since the effects of BMDMs in vitro are predictive of CNS macrophage responses, our results open new therapeutic avenues for managing maladaptive CNS inflammation and support utilization of IL-10/12 cytokine profiles as indicators of macrophage polarization and neurotoxicity.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Azithromycin; Cell Line, Tumor; Inflammation; Interleukin-10; Interleukin-12; Macrophage Activation; Macrophages; Mice, Inbred C57BL; Neurons; Neuroprotective Agents

Adult patients with chronic productive cough of unknown cause are commonly seen in respiratory clinics. We have previously described a subgroup of these patients who have a short-lived response to standard antibiotic treatment but a prolonged response to 3 months of low-dose azithromycin therapy.. This observational study describes the physiological, radiological and pathological features of this patient cohort along with their response to a 12-week open-label trial of 250 mg azithromycin thrice weekly.. A total of 30 subjects with a mean age of 57 were recruited. The majority demonstrated airway dilatation on high-resolution computed tomography (HRCT) scan without evidence of established bronchiectasis (n = 21) and non-specific chronic inflammatory changes on bronchial biopsy (n = 15/17). Twenty-nine subjects completed 3 months of azithromycin with a significant improvement in median Leicester Cough Questionnaire (LCQ) score (-6.3 points, P < 0.00001), reduction in median 24-h sputum volume (-5.8 mL, P = 0.0003) and improvement in sputum colour (P = 0.003). Patients responsive to azithromycin (n = 22) demonstrated neutrophilic or paucigranulocytic airway inflammation, whereas five subjects with eosinophilic airways inflammation did not respond symptomatically to azithromycin.. We describe a cohort of patients with chronic productive cough not adequately described by existing disease labels whose symptoms responded well to low-dose azithromycin. Many of the features are similar to the paediatric condition protracted bacterial bronchitis.

Topics: Anti-Bacterial Agents; Azithromycin; Chronic Disease; Cough; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Inflammation; Male; Middle Aged; Neutrophils; Sputum; Tomography, X-Ray Computed; Treatment Outcome

Human rhinovirus (RV) is a common upper and lower respiratory pathogen in lung allograft recipients causing respiratory tract exacerbation and contributing towards allograft dysfunction and long-term lung decline. In this study, we tested the hypothesis that RV could infect both the small and large airways, resulting in significant inflammation.. Matched large and small airway epithelial cells (AEC) were obtained from five lung allograft recipients. Primary cultures were established, and monolayers were infected with RV1b over time with varying viral titre. Cell viability, receptor expression, viral copy number, apoptotic induction and inflammatory cytokine production were also assessed at each region. Finally, the effect of azithromycin on viral replication, induction of apoptosis and inflammation was investigated.. RV infection caused significant cytotoxicity in both large AEC (LAEC) and small AEC (SAEC), and induced a similar apoptotic response in both regions. There was a significant increase in receptor expression in the LAEC only post viral infection. Viral replication was elevated in both LAEC and SAEC, but was not significantly different. Prophylactic treatment of azithromycin reduced viral replication and dampened the production of inflammatory cytokines post-infection.. Our data illustrate that RV infection is capable of infecting upper and lower AEC, driving cell death and inflammation. Prophylactic treatment with azithromycin was found to mitigate some of the detrimental responses. Findings provide further support for the prophylactic prescription of azithromycin to minimize the impact of RV infection.

Topics: Alveolar Epithelial Cells; Anti-Bacterial Agents; Apoptosis; Azithromycin; Cell Survival; Cells, Cultured; Cytokines; Humans; Inflammation; Lung Transplantation; Picornaviridae Infections; Respiratory Tract Infections; Rhinovirus; Virus Replication

Topics: Allografts; Azithromycin; Common Cold; Humans; Inflammation; Rhinovirus

Inflammation contributes to neonatal hypoxic-ischemic brain injury pathogenesis. We evaluated the neuroprotective efficacy of azithromycin, a safe, widely available antibiotic with anti-inflammatory properties, in a neonatal rodent hypoxic-ischemic brain injury model.. Seven-day-old rats underwent right carotid artery ligation followed by 90-min 8% oxygen exposure; this procedure elicits quantifiable left forepaw functional impairment and right cerebral hemisphere damage. Sensorimotor function (vibrissae-stimulated forepaw placing, grip strength) and brain damage were compared in azithromycin- and saline-treated littermates 2-4 weeks later. Multiple treatment protocols were evaluated (variables included doses ranging from 15 to 45 mg/kg; treatment onset 15 min to 4 h post-hypoxia, and comparison of 1 vs. 3 injections).. All azithromycin doses improved function and reduced brain damage; efficacy was dose dependent, and declined with increasing treatment delay. Three azithromycin injections, administered over 48 h, improved performance on both function measures and reduced brain damage more than a single dose.. In this neonatal rodent model, azithromycin improved functional and neuropathology outcomes. If supported by confirmatory studies in complementary neonatal brain injury models, azithromycin could be an attractive candidate drug for repurposing and evaluation for neonatal neuroprotection in clinical trials.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Brain; Carotid Arteries; Disease Models, Animal; Drug Repositioning; Female; Hypoxia-Ischemia, Brain; Inflammation; Male; Neuroprotection; Neuroprotective Agents; Rats; Rats, Wistar

Trachoma, caused by Chlamydia trachomatis, remains the leading infectious cause of blindness worldwide. Persistence and progression of the resulting clinical disease appears to be an immunologically mediated process. Azithromycin, which is distributed at the community level for trachoma control, has immunomodulatory properties. We investigated the impact of one round of oral azithromycin on conjunctival immune responses, C. trachomatis infection and clinical signs three- and six- months post treatment relative to three pre-treatment time-points.. A cohort of children aged 6 to 10 years were recruited from a trachoma endemic region of northern Tanzania and were visited five times in a 12-month period. They were examined for clinical signs of trachoma and conjunctival swabs were collected for laboratory analysis. C. trachomatis infection was detected and the expression of 46 host genes was quantified using quantitative PCR. All community members were offered azithromycin treatment immediately after the six-month timepoint according to international guidelines.. The prevalence of C. trachomatis infection and inflammatory disease signs were significantly reduced three- and six- months post-mass drug administration (MDA). C. trachomatis infection was strongly associated with clinical signs at all five time-points. A profound anti-inflammatory effect on conjunctival gene expression was observed 3 months post-MDA, however, gene expression had largely returned to pre-treatment levels of variation by 6 months. This effect was less marked, but still observed, after adjusting for C. trachomatis infection and when the analysis was restricted to individuals who were free from both infection and clinical disease at all five time-points. Interestingly, a modest effect was also observed in individuals who did not receive treatment.. Conjunctival inflammation is the major clinical risk factor for progressive scarring trachoma, therefore, the reduction in inflammation associated with azithromycin treatment may be beneficial in limiting the development of potentially blinding disease sequelae. Future work should seek to determine whether this effect is mediated directly through inhibition of pro-inflammatory intracellular signalling molecules, through reductions in concurrent, sub-clinical infections, and/or through reduction of infection exposure.

Topics: Anti-Bacterial Agents; Azithromycin; Blindness; Child; Chlamydia Infections; Chlamydia trachomatis; Cicatrix; Cohort Studies; Conjunctiva; Female; Gene Expression; Humans; Inflammation; Linear Models; Logistic Models; Male; Mass Drug Administration; Prevalence; Tanzania; Trachoma

Chlamydia infection remains the leading sexually-transmitted bacterial infection worldwide, causing damaging sequelae such as tubal scarring, infertility and ectopic pregnancy. As infection is often asymptomatic, prevention via vaccination is the optimal strategy for disease control. Vaccination strategies aimed at preventing bacterial infection have shown some promise, although these strategies often fail to prevent damaging inflammatory pathology when Chlamydia is encountered. Using a murine model of Chlamydia muridarum genital infection, we employed two established independent models to compare immune responses underpinning pathologic development of genital Chlamydia infection. Model one uses antibiotic treatment during infection, with only early treatment preventing pathology. Model two uses a plasmid-cured variant strain of C. muridarum that does not cause pathologic outcomes like the plasmid-containing wild-type counterpart. Using these infection models, contrasted by the development of pathology, we identified an unexpected role for macrophages. We observed that mice showing signs of pathology had greater numbers of activated macrophages present in the oviducts. This may have been due to early differences in macrophage activation and proinflammatory signaling leading to persistent or enhanced infection. These results provide valuable insight into the cellular mechanisms driving pathology in Chlamydia infection and contribute to the design and development of more effective vaccine strategies for protection against the deleterious sequelae of Chlamydia infection of the female reproductive tract.

Topics: Animals; Azithromycin; Chlamydia Infections; Chlamydia muridarum; Chronic Disease; Cytokines; Drug Resistance, Bacterial; Fallopian Tubes; Female; Gene Expression Regulation; Inflammation; Inflammation Mediators; Macrophages; Mice, Inbred BALB C; Oviducts

Respiratory syncytial virus (RSV) infection is an important cause of morbidity and mortality in vulnerable populations. Macrolides have received considerable attention for their anti-inflammatory actions beyond their antibacterial effect. We hypothesize that prophylactic azithromycin will be effective in reducing the severity of RSV infection in a mouse model.. Four groups of BALB/c mice were studied for 8 days: Control (C), RSV-infected (R), early prophylaxis with daily azithromycin from days 1 to 8, (E), and late prophylaxis with daily azithromycin from days 4 to 8 (L). Mice were infected with RSV on day 4, except for the control group. All groups were followed for a total of 8 days when bronchoalveolar lavage cell count and cytokines levels were measured. Mouse weight, histopathology, and mortality data were obtained.. Prophylactic azithromycin significantly attenuated post-viral weight loss between group R and both groups E and L (P = 0.0236, 0.0179, respectively). IL-6, IL-5, and Interferon-Gamma were significantly lower in group L (P = 0.0294, 0.0131, and 0.0056, respectively) compared with group R. The total cell count was significantly lower for group L as compared with group R (P < 0.05). Mortality was only observed in group R (8%). Lung histology in the prophylactic groups showed diminished inflammatory infiltrates and cellularity when compared with group R.. Prophylactic azithromycin effectively reduced weight loss, airway inflammation, cytokine levels and mortality in RSV-infected mice. These results support the rationale for future clinical trials to evaluate the effects of prophylactic azithromycin for RSV infection.

Topics: Animals; Antibiotic Prophylaxis; Azithromycin; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Inflammation; Lung; Mice; Mice, Inbred BALB C; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses

As highly trachoma-endemic countries approach elimination, some districts will have prevalences of trachomatous inflammation-follicular in 1-9-year-olds (TF1-9) of 5.0-9.9%. The World Health Organization (WHO) previously recommended that in such districts, TF prevalence be assessed in each sub-district (groupings of at least three villages), with three rounds of azithromycin treatment offered to any sub-district in which TF≥10%. Given the large number of endemic districts worldwide and the human and financial resources required to conduct surveys, this recommendation may not be practical. In a group of 8 Malawi districts with baseline TF prevalences of 5.0-9.9%, the Malawi Ministry of Health administered one round of azithromycin mass treatment, to the whole of each district, achieving mean coverage of ~80%. Here, we report impact surveys conducted after that treatment.. We undertook population-based trachoma surveys in 18 evaluation units of the 8 treated districts, at least 6 months after the MDA. The standardized training package and survey methodologies of Tropical Data, which conform to WHO recommendations, were used.. Each of the 18 evaluation units had a TF1-9 prevalence <5.0%.. The study demonstrates that in Malawi districts with TF of 5.0-9.9%, one round of azithromycin MDA with ~80% coverage associates with a reduction in TF prevalence to <5%. Further evidence for this approach should be collected elsewhere.

Topics: Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Cross-Sectional Studies; Humans; Infant; Inflammation; Malawi; Mass Drug Administration; Prevalence; Surveys and Questionnaires; Trachoma; World Health Organization

Sepsis is a life-threatening systemic inflammatory condition triggered as a result of an excessive host immune response to infection. In the past, immunomodulators have demonstrated a protective effect in sepsis. Azithromycin (a macrolide antibiotic) has immunomodulatory activity and was therefore evaluated in combination with ceftriaxone in a clinically relevant murine model of sepsis induced by cecal ligation and puncture (CLP). First, mice underwent CLP and 3 h later were administered the vehicle or a subprotective dose of ceftriaxone (100 mg/kg of body weight subcutaneously) alone or in combination with an immunomodulatory dose of azithromycin (100 mg/kg intraperitoneally). Survival was monitored for 5 days. In order to assess the immunomodulatory activity, parameters such as plasma and lung cytokine (interleukin-6 [IL-6], IL-1β, tumor necrosis factor alpha) concentrations, the plasma glutathione (GSH) concentration, plasma and lung myeloperoxidase (MPO) concentrations, body temperature, blood glucose concentration, and total white blood cell count, along with the bacterial load in blood, peritoneal lavage fluid, and lung homogenate, were measured 18 h after CLP challenge. Azithromycin in the presence of ceftriaxone significantly improved the survival of CLP-challenged mice. Further, the combination attenuated the elevated levels of inflammatory cytokines and MPO in plasma and lung tissue and increased the body temperature and blood glucose and GSH concentrations, which were otherwise markedly decreased in CLP-challenged mice. Ceftriaxone produced a significant reduction in the bacterial load, while coadministration of azithromycin did not produce a further reduction. Therefore, the survival benefit offered by azithromycin was due to immunomodulation and not its antibacterial action. The findings of this study indicate that azithromycin, in conjunction with appropriate antibacterial agents, could provide clinical benefits in sepsis.

Topics: Animals; Azithromycin; Bacterial Load; Ceftriaxone; Disease Models, Animal; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Female; Glutathione; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Lung; Mice; Sepsis; Tumor Necrosis Factor-alpha

Acute myocardial infarction (MI) is a primary cause of worldwide morbidity and mortality. Macrophages are fundamental components of post-MI inflammation. Pro-inflammatory macrophages can lead to adverse cardiac remodeling and heart failure while anti-inflammatory/reparative macrophages enhance tissue healing. Shifting the balance between pro-inflammatory and reparative macrophages post-MI is a novel therapeutic strategy. Azithromycin (AZM), a commonly used macrolide antibiotic, polarizes macrophages towards the anti-inflammatory phenotype, as shown in animal and human studies. We hypothesized that AZM modulates post-MI inflammation and improves cardiac recovery.. Male WT mice (C57BL/6, 6-8 weeks old) were treated with either oral AZM (160 mg/kg/day) or vehicle (control) starting 3 days prior to MI and continued to day 7 post-MI. We observed a significant reduction in mortality with AZM therapy. AZM-treated mice showed a significant decrease in pro-inflammatory (CD45+/Ly6G-/F4-80+/CD86+) and increase in anti-inflammatory (CD45+/Ly6G-/F4-80+/CD206+) macrophages, decreasing the pro-inflammatory/anti-inflammatory macrophage ratio in the heart and peripheral blood as assessed by flow cytometry and immunohistochemistry. Macrophage changes were associated with a significant decline in pro- and increase in anti-inflammatory cytokines. Mechanistic studies confirmed the ability of AZM to shift macrophage response towards an anti-inflammatory state under hypoxia/reperfusion stress. Additionally, AZM treatment was associated with a distinct decrease in neutrophil count due to apoptosis, a known signal for shifting macrophages towards the anti-inflammatory phenotype. Finally, AZM treatment improved cardiac recovery, scar size, and angiogenesis.. Azithromycin plays a cardioprotective role in the early phase post-MI through attenuating inflammation and enhancing cardiac recovery. Post-MI treatment and human translational studies are warranted to examine the therapeutic applications of AZM.

Topics: Administration, Oral; Animals; Antigens, Differentiation; Azithromycin; Cardiotonic Agents; Cytokines; Inflammation; Macrophages; Male; Mice; Myocardial Infarction; Neovascularization, Physiologic

Patients with more severe chronic obstructive pulmonary disease frequently experience exacerbations and it is estimated that up to 50% of these exacerbations are associated with bacterial infections. The mainstay treatment for these infection-related exacerbations constitutes the administration of glucocorticoids, alone or in combination with antibiotics. A recent line of evidence demonstrates that many hormones including the steroid beclomethasone can also directly affect bacterial growth, virulence, and antibiotic resistance. The effect of these regimens on the release of potentially virulent and toxic membrane vesicles (MVs) is at present unclear. In this study, we determined the effect of several pharmacological agents on MVs release by and bacterial growth of common respiratory pathogens. We found that neither the release of MVs nor the bacterial growth was affected by the glucocorticoids budesonide and fluticasone. The macrolide antibiotic azithromycin only inhibited the growth of Moraxella catarrhalis but no effects were observed on bacterial MV release at a concentration that is achieved locally in the epithelial lining on administration. The macrophage pro-inflammatory response to MVs was significantly reduced after treatment with budesonide and fluticasone but not by azithromycin treatment. Our findings suggest that these glucocorticoids may have a positive effect on infection-related inflammation although the bacterial growth and MV release remained unaffected.

Topics: Anti-Bacterial Agents; Azithromycin; Bacteria; Bacterial Infections; Beclomethasone; Budesonide; Cell Line; Cell-Derived Microparticles; Fluticasone; Glucocorticoids; Humans; Inflammation; Macrophages

Azithromycin, an antibiotic used for multiple infectious disorders, exhibits anti-inflammatory effects, but the molecular basis for this activity is not well characterized. Azithromycin inhibits IL-1β-mediated inflammation that is dependent, in part, on inflammasome activity. Here, we investigated the effects of azithromycin on the NACHT, LRR, and PYD domains-containing protein 3 (NALP3) protein, which is the sensing component of the NALP3 inflammasome, in human monocytes.. THP-1 cells were treated with azithromycin alone, LPS alone, or both. NALP3 and IL-1β protein levels were determined by immunoblotting. NLRP3 gene (encoding NALP3) transcript levels were determined by quantitative qPCR. In order to measure NLRP3 transcript decay, actinomycin D was used to impair gene transcription. THP-1 Lucia cells which contain an NF-κB responsive luciferase element were used to assess NF-κB activity in response to azithromycin, LPS, and azithromycin/LPS by measuring luminescence. To confirm azithromycin's effects on NLRP3 mRNA and promoter activity conclusively, HEK cells were lipofected with luciferase reporter constructs harboring either the 5' untranslated region (UTR) of the NLRP3 gene which included the promoter, the 3' UTR of the gene, or an empty plasmid prior to treatment with azithromycin and/or LPS, and luminescence was measured.. Azithromycin decreased IL-1β levels and reduced NALP3 protein levels in LPS-stimulated THP-1 monocytes through a mechanism involving decreased mRNA stability of the NALP3 - coding NLRP3 gene transcript as well as by decreasing NF-κB activity. Azithromycin accelerated NLRP3 transcript decay confirmed by mRNA stability and 3'UTR luciferase reporter assays, and yet the antibiotic had no effect on NLRP3 promoter activity in cells containing a 5' UTR reporter.. These studies provide a unique mechanism whereby azithromycin exerts immunomodulatory actions in monocytes by destabilizing mRNA levels for a key inflammasome component, NALP3, leading to decreased IL-1β-mediated inflammation.

Topics: Anti-Bacterial Agents; Azithromycin; Cell Line; HEK293 Cells; Humans; Inflammasomes; Inflammation; Monocytes; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Protein Stability; RNA, Messenger

This study aimed to investigate the potential effects of the combination therapy of irsogladine maleate (IM) and azithromycin (AZM) on the inflammation in lipopolysaccharide (LPS)-induced gingival epithelial cells.. Human gingival epithelial cell OBA-9 was stimulated by LPS to construct the periodontitis model, followed by the treatment of irsogladine maleate (IM) or azithromycin (AZM) with different concentration. Transepithelial electrical resistance (TER) of cells in each group was analyzed, and qRT-PCR and western blotting were used to detect the expressions of inflammatory cytokines. Immunofluorescence staining was performed to detect the protein expression.. The TER for cells was significantly decreased while the inflammatory cytokines expressions including IL-6, IL-8, IL-1β and TNF-α were all significantly increased by LPS compared to the control (P<0.05). However, TER was increased significantly, whereas the cytokine levels were decreased by IM or AZM, but these effects was more apparent in cells treated with IM and AZM combination (P<0.01). Moreover, E-cadherin and vimentin expressions were more positive in the IM and AZM group than in the other groups. The application of ERK and P38 MAPK inhibitors reversed the effects of LPS on cell inflammatory cytokine production and cell TER.. This study revealed that the combination therapy of IM and AZM performed excellent effects on preventing the inflammatory progression of periodontitis.

Topics: Anti-Bacterial Agents; Anti-Ulcer Agents; Azithromycin; Blotting, Western; Cadherins; Cell Line; Cytokines; Disease Progression; Drug Synergism; Drug Therapy, Combination; Epithelial Cells; Gingiva; Humans; Inflammation; Lipopolysaccharides; Periodontitis; Reverse Transcriptase Polymerase Chain Reaction; Triazines; Vimentin

Azithromycin can benefit treating allergic airway inflammation and remodeling. In the present study, we hypothesized that azithromycin alleviated airway epithelium injury through inhibiting airway epithelium apoptosis via down regulation of caspase-3 and Bax/Bcl2 ratio in vivo and in vitro.. Ovalbumin induced rat asthma model and TGF-β1-induced BEAS-2B cell apoptosis model were established, respectively. In vivo experiments, airway epithelium was stained with hematoxylin and eosin (HE) and periodic acid-Schiff (PAS) to histologically evaluate the airway inflammation and remodeling. Airway epithelium apoptotic index (AI) was further analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), while expression of apoptosis related gene (Bax, Bcl2, Caspase-3) in lungs were measured by qRT-PCR and western blotting, respectively. In vitro experiments, apoptosis were evaluated by Flow cytometry (FCM) and TUNEL. Above apoptosis related gene were also measured by qRT-PCR and western blotting.. Compared with the OVA group, azithromycin significantly reduced the inflammation score, peribronchial smooth muscle layer thickness, epithelial thickening and goblet cell metaplasia (P<0.05), and effectively suppressed AI of airway epithelium (P<0.05). Moreover, the increasing mRNA and protein expressions of Caspase-3 and Bax/Bcl-2 ratio in lung tissue were all significantly decreased in azithromycin-treated rats (P<0.05). In vitro, azithromycin significantly suppressed TGF-β1-induced BEAS-2B cells apoptosis (P<0.05) and reversed TGF-β1 elevated Caspase-3 mRNA level and Bax/Bcl-2 ratio (P<0.05).. Azithromycin is an attractive treatment option for reducing airway epithelial cell apoptosis by improving the imbalance of Bax/Bcl-2 ratio and inhibiting Caspase-3 level in airway epithelium.

Topics: Airway Remodeling; Animals; Apoptosis; Asthma; Azithromycin; bcl-2-Associated X Protein; Caspase 3; Cell Line; Endothelium, Vascular; Epithelium; Flow Cytometry; In Situ Nick-End Labeling; Inflammation; Lung; Male; Ovalbumin; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1

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

Acute otitis media, inflammation of the middle ear, is the most common bacterial infection in children and, as a consequence, is the most common reason for antimicrobial prescription to this age group. There is currently no effective vaccine for the principal pathogen involved, non-typeable Haemophilus influenzae (NTHi). The most frequently used and widely accepted experimental animal model of middle ear infection is in chinchillas, but mice and gerbils have also been used. We have established a robust model of middle ear infection by NTHi in the Junbo mouse, a mutant mouse line that spontaneously develops chronic middle ear inflammation in specific pathogen-free conditions. The heterozygote Junbo mouse (Jbo/+) bears a mutation in a gene (Evi1, also known as Mecom) that plays a role in host innate immune regulation; pre-existing middle ear inflammation promotes NTHi middle ear infection. A single intranasal inoculation with NTHi produces high rates (up to 90%) of middle ear infection and bacterial titres (10(4)-10(5) colony-forming units/µl) in bulla fluids. Bacteria are cleared from the majority of middle ears between day 21 and 35 post-inoculation but remain in approximately 20% of middle ears at least up to day 56 post-infection. The expression of Toll-like receptor-dependent response cytokine genes is elevated in the middle ear of the Jbo/+ mouse following NTHi infection. The translational potential of the Junbo model for studying antimicrobial intervention regimens was shown using a 3 day course of azithromycin to clear NTHi infection, and its potential use in vaccine development studies was shown by demonstrating protection in mice immunized with killed homologous, but not heterologous, NTHi bacteria.

Topics: Animals; Azithromycin; Disease Models, Animal; Haemophilus Infections; Haemophilus influenzae; Heterozygote; Immunity, Innate; Inflammation; Mice; Mice, Inbred C3H; Mice, Mutant Strains; Microspheres; Mutation; Otitis Media; Signal Transduction; Stem Cells

Topics: Amoxicillin; Anti-Bacterial Agents; Azithromycin; Biological Availability; Dental Implants; Humans; Inflammation

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

We hypothesized that if internalization of Staphylococcus aureus could be blocked by using cytochalasin D (an inhibitor of phagocytosis and phagolysosome fusion), then the intracellular entry and survival of the pathogen in host's phagocytic cells recruited to the inflammatory site can be restricted. At the same time, if we use antimicrobial agents (e.g., ciprofloxacin and azithromycin) having potent intracellular and extracellular microbicidal activity against the bacterium that have not entered into the phagosome and remains adhered to the phagocytic cell membrane, then they can be eradicated from the site of infection without compromising the host cell. To validate this, role of ciprofloxacin (CIP) and azithromycin (AZM) in eliminating S. aureus by suppressing the phagocytic activity of macrophages with cytochalasin D before infection was investigated. CIP and AZM were used either alone or in combination with cytochalasin D. Supernatant and lysate obtained from the culture of macrophages were used for quantification of reactive oxygen species, lysozymes, antioxidant enzymes, and cytokines produced. Azithromycin was better than ciprofloxacin in combination with cytochalasin D for eradicating S. aureus and regulating cytokine release. Further studies are required for ensuring proper delivery of this combination at the site of infection.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antioxidants; Azithromycin; Ciprofloxacin; Cytochalasin D; Drug Therapy, Combination; Glutathione; Hydrogen Peroxide; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-6; Macrophages; Male; Mice; Microbial Sensitivity Tests; Muramidase; Phagocytosis; Staphylococcal Infections; Staphylococcus aureus; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Chlamydia psittaci is a zoonotic bacterium with a wide host range that can cause respiratory disease in humans and cattle. In the present study, effects of treatment with macrolides and quinolones applied alone or in combination with rifampicin were tested in a previously established bovine model of respiratory C. psittaci infection. Fifty animals were inoculated intrabronchially at the age of 6-8 weeks. Seven served as untreated controls, the others were assigned to seven treatment groups: (i) rifampicin, (ii) enrofloxacin, (iii) enrofloxacin + rifampicin, (iv) azithromycin, (v) azithromycin + rifampicin, (vi) erythromycin, and (vii) erythromycin + rifampicin. Treatment started 30 hours after inoculation and continued until 14 days after inoculation (dpi), when all animals were necropsied. The infection was successful in all animals and sufficient antibiotic levels were detected in blood plasma and tissue of the treated animals. Reisolation of the pathogen was achieved more often from untreated animals than from other groups. Nevertheless, pathogen detection by PCR was possible to the same extent in all animals and there were no significant differences between treated and untreated animals in terms of local (i.e., cell count and differentiation of BALF-cells) and systemic inflammation (i.e. white blood cells and concentration of acute phase protein LBP), clinical signs, and pathological findings at necropsy. Regardless of the reduced reisolation rate in treated animals, the treatment of experimentally induced respiratory C. psittaci infection with enrofloxacin, azithromycin or erythromycin alone or in combination with rifampicin was without obvious benefit for the host, since no significant differences in clinical and pathological findings or inflammatory parameters were detected and all animals recovered clinically within two weeks.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Cattle; Chlamydophila psittaci; Disease Models, Animal; Enrofloxacin; Erythromycin; Fluoroquinolones; Inflammation; Macrolides; Male; Psittacosis; Rifampin

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

Polyacrylamide hydrogel has in the last decade gained popularity as an injectable filler for facial augmentation due to its features of non-toxicity, biocompatibility, safety profile, and immediate effect. However, as all types of injections carry the risk of infection and since the polyacrylamide hydrogel is a non-degradable implant, the possibility of bacterial biofilm formation exists. Theoretically, the risk of infection and subsequent biofilm formation can be avoided by using prophylactic antibiotic treatment prior to the time of injection.. This retrospective study of outcomes following polyacrylamide hydrogel injections includes 657 subjects from one centre, which had facial injections from 2001 and 2011. Until 2007 prophylactic antibiotics were not given prior to treatment, but in September 2007 a single oral dose of azithromycin (Zitromax) and moxifloxacin (Avelox) was introduced as prophylactic antibiotics. A total of 496 subjects were injected before 2007 without antibiotic prophylactic treatment, and 161 subjects received these two antibiotics prior to treatment from September 2007.. The prophylactic antibiotics (azithromycin and moxifloxacin) significantly reduced the incidence of clinical signs of inflammation/infections from 7 to 2% (P=0.03).. Even though the incidence of inflammation/infections following injection of polyacrylamide hydrogel is relatively low, it may be reduced further by using prophylactic antibiotic treatment. Based on our experience, we recommend prophylactic antibiotics to patients who have facial augmentation with polyacrylamide hydrogel in order to avoid infection and risk of biofilm formation due to contamination during injection with naturally occurring micro flora from skin and lips.

Topics: Acrylic Resins; Adolescent; Adult; Aged; Anti-Bacterial Agents; Antibiotic Prophylaxis; Azithromycin; Bacterial Infections; Biofilms; Cosmetic Techniques; Face; Female; Fluoroquinolones; Humans; Incidence; Inflammation; Injections; Male; Middle Aged; Moxifloxacin; Retrospective Studies; Young Adult

Any inflammatory response following corneal transplantation may induce rejection and irreversible graft failure. The purpose of this study is to analyze the anti-inflammatory effect of azithromycin (AZM) following experimental keratoplasty in rats.. Corneal transplants were performed between Fisher-donor and Lewis-recipient rats. Recipients were postoperatively treated three times daily with AZM, miglyol, ofloxacin or dexamethasone eye drops. As an additional control, AZM was applied following syngeneic keratoplasty. Furthermore, short-term treatments with AZM for seven days perioperatively or with AZM only three days prior to the transplantation were compared to appropriate controls. All transplants were monitored clinically for opacity, edema, and vascularization. Infiltrating CD45(+), CD4(+), CD8(+), CD25(+), CD161(+) and CD163(+) cells were quantified via immunohistochemistry.. AZM significantly promoted corneal graft survival compared with miglyol or ofloxacin treatment. This effect was comparable to topical dexamethasone. No adverse AZM effect was observed. Histology confirmed a significant reduction of infiltrating leukocytes. The short-term application of AZM for three days prior to transplantation or for seven days perioperatively reduced corneal graft rejection significantly compared with the controls.. Along with antibiotic properties, topical AZM has a strong anti-inflammatory effect. Following keratoplasty, this effect is comparable to topical dexamethasone without the risk of steroid-induced adverse effects. Short-term treatment with AZM three days prior to the transplantation was sufficient to promote graft survival in the rat keratoplasty model. We therefore suggest further assessing the anti-inflammatory function of topical AZM following keratoplasty in humans.

Topics: Administration, Topical; Adrenal Cortex Hormones; Allografts; Animals; Anti-Inflammatory Agents; Azithromycin; Cornea; Corneal Transplantation; Female; Graft Survival; Inflammation; Keratoplasty, Penetrating; Models, Animal; Rats

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

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Bronchiolitis Obliterans; Humans; Inflammation; Lung Diseases; Lung Transplantation; Placebos; Retrospective Studies

Epidemiological and animal model studies suggest that sequelae of genital Chlamydia trachomatis infection are more often associated with second or subsequent infections than with initial infection. Further, in order to establish an acute or long-term persistent infection, C. trachomatis develops several strategies to circumvent host immune responses. Hence, resolution of the C. trachomatis infection may require modulation of host factors especially during persistent or chronic infection. Moreover, azithromycin treatment has been reported to possess anti-inflammatory properties but its mechanism of action is still not elucidated. Therefore, in order to better understand the effect of azithromycin in chronic conditions, our aim was to study changes in expression of key genes associated with inflammatory cytokines and receptors, mitogen-activated protein kinase (MAPK) signaling pathway, and apoptosis pathway before and after therapy with azithromycin in infertile women with recurrent C. trachomatis infection. Real-time polymerase chain reaction was performed to study inflammatory cytokines and receptors, MAPK signaling pathway, and apoptosis pathway before and after therapy with azithromycin in infertile women with recurrent C. trachomatis infection. Further, effect of azithromycin on activation of extracellular signal-regulated kinase was studied in epithelial cells by western blotting. Chemokine (C-C motif) ligand 2 (CCL2), CCL5, chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL5, CXCL9, interleukin-1B (IL-1B), IL-8, baculoviral IAP repeat-containing 3 (BIRC3), myeloid cell leukemia sequence 1 (MCL1), and MAPK1 were downregualted after azithromycin treatment. In addition, phosphorylation of extracellular signal-regulated kinase was inhibited after azithromycin treatment in epithelial cells obtained from women with recurrent infection. Hence, our data suggest that azithromycin with its properties apart from antibacterial activity may contribute to its therapeutic potential in treatment of chronic recurrent infection in infertile women.

Topics: Anti-Bacterial Agents; Apoptosis; Azithromycin; Chemokines; Chlamydia Infections; Chlamydia trachomatis; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression Regulation; HeLa Cells; Humans; Infertility, Female; Inflammation; MAP Kinase Signaling System; Phosphorylation; Receptors, Cytokine; Recurrence; Reverse Transcriptase Polymerase Chain Reaction

Inflammation-driven immune dysfunction supports the development of several chronic human disorders including inflammatory bowel diseases and rheumatoid arthritis. Macrolides are effective antibiotics endowed with immunomodulatory effects. In this study we report the chemical synthesis and the pharmacological characterization of CSY0073, a non-antibiotic derivative of azithromycin. CSY0073 was tested for efficacy in two experimental models of colitis induced by administering mice with dextran sulfate (DSS) and trinitrobenzene sulphonic acid (TNBS) and in collagen induced arthritis. Like azithromycin, CSY0073 improved clinical, macroscopic and histopathological scores in mice administered DSS (12.5μmol/kg/day p.o.) and TNBS (45μmol/kg/day p.o.). When administered to TNBS-treated mice, CSY0073 effectively attenuated influx of neutrophils and macrophages into the colonic mucosa and reduced the intestinal expression pro-inflammatory cytokines TNFα, IL-2 and IFNγ. CSY0073 (0.1 to 10μM) counter-regulated TNFα, IFNγ, IL-12 and IL-23 release caused by exposure of mouse spleen monocytes and CD11b+ cells isolated from the colonic lamina propria to endotoxin. CSY0073 (25μmol/kg/day) reduced clinical scores in the collagen induced murine model of rheumatoid arthritis. In myeloid cells, CSY0073 (10μM) prevented the nuclear translocation of the p65 subunit of NF-κB and its binding to canonical NF-κB responsive elements. In summary, we report a novel class of non-antibiotic 14-member macrocycles with anti-inflammatory and immune-modulatory effects. CSY0073, the prototype of this new class of macrolides exerts counter-regulatory activity on NF-κB signaling. This study suggests the exploitation of non-antibiotic macrolides in the treatment of inflammatory disorders characterized by immune dysfunction.

Topics: Animals; Anti-Inflammatory Agents; Arthritis; Azithromycin; CD11b Antigen; Colitis; Collagen; Dextran Sulfate; Disease Models, Animal; Drug Discovery; Female; Humans; Immunologic Factors; Inflammation; Inflammatory Bowel Diseases; Male; Mice; Mucous Membrane; NF-kappa B; Signal Transduction; Trinitrobenzenesulfonic Acid

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Blood Cell Count; Endotoxemia; Inflammation; Interleukin-6; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Serum Amyloid A Protein

Toxoplasma gondii is an important pathogen which may cause fetal infection if primary infection. Our previous studies have used human choriocarcinoma trophoblastic cells (BeWo cell line) as experimental model of T. gondii infection involving placental microenvironment. This study aimed to examine the effects of azithromycin and spiramycin against T. gondii infection in BeWo cells. Cells were treated with different concentrations of the macrolide antibiotics and analyzed first for cell viability using thiazolyl blue tetrazole (MTT) assay. As cell viability was significantly decreased with drug concentrations higher than 400 μg/mL, the concentration range used in further experiments was from 50 to 400 μg/mL. The number of infected cells and intracellular replication of T. gondii decreased after treatment with each drug. The infection induced up-regulation of the macrophage migration inhibitory factor (MIF), which was also enhanced in infected cells after treatment with azithromycin, but not with spiramycin. Analysis of the cytokine profile showed increase TNF-α, IL-10 and IL-4 production, but decreased IFN-γ levels, were detected in infected cells and treated with each drug. In conclusion, treatment of human trophoblastic BeWo cells with with azithromycin or spiramycin is able to control the infection and replication of T. gondii. In addition, treatment with these macrolides, especially with azityromycin induces an anti-inflammatory response and high MIF production, which can be important for the establishment and maintenance of a viable pregnancy during T. gondii infection.

Topics: Animals; Anti-Inflammatory Agents; Azithromycin; Cell Line; Cell Survival; Female; Humans; Inflammation; Mice; Pregnancy; Spiramycin; Toxoplasma; Toxoplasmosis; Trophoblasts

This protocol describes microsphere-based protease assays for use in flow cytometry and high-throughput screening. This platform measures a loss of fluorescence from the surface of a microsphere due to the cleavage of an attached fluorescent protease substrate by a suitable protease enzyme. The assay format can be adapted to any site or protein-specific protease of interest and results can be measured in both real time and as endpoint fluorescence assays on a flow cytometer. Endpoint assays are easily adapted to microplate format for flow cytometry high-throughput analysis and inhibitor screening.

Topics: Animals; Biotinylation; Flow Cytometry; Fluorescence Resonance Energy Transfer; Green Fluorescent Proteins; High-Throughput Screening Assays; Humans; Inflammation; Kinetics; Microspheres; Peptide Hydrolases; Peptides; Reproducibility of Results; Temperature

The aim of this study was to investigate the effect of the macrolide antibiotic azithromycin on mucosal changes and colonic bacterial load in a murine model of colitis.. Colitis was induced in CD1 mice using enema of 0.2% solution of dinitrofluorobenzene, combined with skin sensitization. Four experimental groups of animals (N = 10 per group) were treated with 50 mg/kg/day azithromycin (AZ) or metronidazole (MN) perorally, starting 24 h before (AZ-1, MN-1) or 6 h after (AZ+1, MN+1) induction of colitis and for consecutive 5 days. Additional experimental mice group was treated with 10 mg/kg/day methylprednisolone intraperitoneally after induction of experimental colitis in the same manner (MP). Two control groups consisted of healthy animals (C) that received the challenge enema with phosphate-buffered saline (PBS) and animals with experimental colitis (chall) treated with equivolume of PBS perorally. Clinical score (0-5) and histopathologic score (0-30) were used to assess inflammatory changes, and colon washings were used to determine changes in bacterial load.. The anti-inflammatory effect of azithromycin did not differ from the effect of methylprednisolone, when compared with control group with experimental colitis. Metronidazole did not show a significant anti-inflammatory effect. Number of colonic bacteria did not differ significantly between control and experimental groups of animals.. We documented the anti-inflammatory effect of azithromycin in a murine model of acute colitis, suggesting that effects were targeted to oxidative burst and on mucosal/bacterial interface, independent of luminal bacterial load. Further studies should be focused on effect of azithromycin on the role of bacterial biofilm in perpetuation of chronic intestinal inflammation.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Colitis; Colon; Inflammation; Male; Methylprednisolone; Metronidazole; Mice; Specific Pathogen-Free Organisms

The majority of asthma exacerbations are caused by rhinovirus. Currently the treatment of asthma exacerbations is inadequate. Previous evidence suggests that macrolide antibiotics have anti-inflammatory and antiviral effects; however, the mechanism is unknown. We investigated the anti-rhinoviral potential of macrolides through the induction of antiviral gene mRNA and protein. Primary human bronchial epithelial cells were pre-treated with the macrolides azithromycin, erythromycin and telithromycin, and infected with minor-group rhinovirus 1B and major-group rhinovirus 16. The mRNA expression of the antiviral genes, type I interferon-β and type III interferon-λ1, interferon-λ2/3, and interferon-stimulated genes (retinoic acid inducible gene I, melanoma differentiation associated gene 5, oligoadenylate synthase, MxA and viperin) and pro-inflammatory cytokines (interleukin (IL)-6 and IL-8), and rhinovirus replication and release were measured. Azithromycin, but not erythromycin or telithromycin, significantly increased rhinovirus 1B- and rhinovirus 16-induced interferons and interferon-stimulated gene mRNA expression and protein production. Furthermore, azithromycin significantly reduced rhinovirus replication and release. Rhinovirus induced IL-6 and IL-8 protein and mRNA expression were not significantly reduced by azithromycin pre-treatment. In conclusion, the results demonstrate that azithromycin has anti-rhinoviral activity in bronchial epithelial cells and, during rhinovirus infection, increases the production of interferon-stimulated genes.

Topics: Animals; Anti-Bacterial Agents; Antiviral Agents; Azithromycin; Bronchi; Cytokines; DNA Primers; DNA, Complementary; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Humans; Inflammation; Interferons; Lung; Picornaviridae Infections; RNA, Messenger

Definitive conclusions regarding the antiinflammatory effects of macrolide antibiotics for treatment of asthma are difficult to formulate since their beneficial effects may be related to their antimicrobial action. We hypothesized that azithromycin possesses distinct antiinflammatory properties and tested this assumption in a noninfectious mouse model of allergic asthma.. To induce allergic airway inflammation, 7-week-old BALB/cJ mice underwent intraperitoneal ovalbumin sensitization on days 0 and 7 followed by an intranasal challenge on day 14. Mice were treated with azithromycin or phosphate-buffered saline (PBS) solution on days 13 through 16. On day 17, airway inflammation was assessed by quantifying leukocytes in the airway, expression of multiple inflammatory mediators in the BAL fluid, and mucous cell metaplasia. In a separate set of experiments, azithromycin or PBS solution treatment were initiated after the ovalbumin challenge. Each experiment was repeated 3 times (a total of 9 to 11 mice in each group).. Compared to treatment with PBS solution, azithromycin attenuated the ovalbumin-dependent airway inflammation. We observed a decrease in total leukocytes in the lung tissue and BAL fluid. In addition, azithromycin attenuated the expression of cytokines (eg, interleukin [IL]-13 and IL-5) and chemokines (eg, CCL2, CCL3, and CCL4) in the BAL fluid and abrogated the extent of mucous cell metaplasia. Similar antiinflammatory effects were observed when azithromycin treatment was initiated after the ovalbumin challenge.. In this noninfectious mouse model of allergic asthma, azithromycin attenuated allergic airway inflammation. These findings demonstrate an antiinflammatory effect of azithromycin and suggest azithromycin may have beneficial effects in treating noninfectious airway inflammatory diseases, including asthma.

Topics: Animals; Asthma; Azithromycin; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Immunoglobulin E; Inflammation; Inflammation Mediators; Leukocyte Count; Lung; Mice; Mice, Inbred BALB C; Mucous Membrane; Ovalbumin; Random Allocation; Reference Values; Risk Factors; Sensitivity and Specificity

Prolonged macrolide antibiotic therapy at low doses improves clinical outcome in patients affected with diffuse panbronchiolitis and cystic fibrosis. Consensus is building that the therapeutic effects are due to anti-inflammatory, rather than anti-microbial activities, but the mode of action is likely complex. To gain insights into how the macrolide azithromycin (AZT) modulates inflammatory responses in airways, well-differentiated primary cultures of human airway epithelia were exposed to AZT alone, an inflammatory stimulus consisting of soluble factors from cystic fibrosis airways, or AZT followed by the inflammatory stimulus. RNA microarrays were conducted to identify global and specific gene expression changes. Analysis of gene expression changes revealed that the AZT treatment alone altered the gene profile of the cells, primarily by significantly increasing the expression of lipid/cholesterol genes and decreasing the expression of cell cycle/mitosis genes. The increase in cholesterol biosynthetic genes was confirmed by increased filipin staining, an index of free cholesterol, after AZT treatment. AZT also affected genes with inflammatory annotations, but the effect was variable (both up- and down-regulation) and gene specific. AZT pretreatment prevented the up-regulation of some genes, such as MUC5AC and MMP9, triggered by the inflammatory stimulus, but the up-regulation of other inflammatory genes, e.g., cytokines and chemokines, such as interleukin-8, was not affected. On the other hand, HLA genes were increased by AZT. Notably, secreted IL-8 protein levels did not reflect mRNA levels, and were, in fact, higher after AZT pretreatment in cultures exposed to the inflammatory stimulus, suggesting that AZT can affect inflammatory pathways other than by altering gene expression. These findings suggest that the specific effects of AZT on inflamed and non-inflamed airway epithelia are likely relevant to its clinical activity, and their apparent complexity may help explain the diverse immunomodulatory roles of macrolides.

Topics: Anti-Bacterial Agents; Azithromycin; Cell Cycle; Epithelial Cells; Gene Expression Profiling; Gene Expression Regulation; Humans; Inflammation; Interleukin-8; Lipid Metabolism; Lipids; Lung; Matrix Metalloproteinase 9; Mucin 5AC; Pseudomonas aeruginosa; Pseudomonas Infections

The bronchial epithelium is a source of mediators that may play a role in the airway inflammation and remodeling of post-transplant obliterative bronchiolitis (OB). Traditional strategies have failed to have an impact on OB. Recent studies have suggested a role for azithromycin in managing the condition. In this study we aimed to determine the effect of azithromycin on LPS-mediated epithelial release of factors relevant to airway neutrophilia and remodeling in a unique population of primary bronchial epithelial cells (PBECs) derived from stable lung allografts.. PBECs were established from bronchial brushings of stable lung transplant recipients and treated with lipopolysaccharide (LPS, 0.1, 1 and 10 microg/ml) for 48 hours. Interleukin-8 (IL-8), granulocyte macrophage colony-stimulating factor (GM-CSF) and vascular endothelial growth factor (VEGF) protein levels were measured by Luminex analyzer. PBECs were then incubated with LPS and azithromycin, and protein levels were again determined.. LPS caused a significant increase in IL-8 and GM-CSF at concentrations of 1 and 10 microg/ml, with no effect on VEGF release. Azithromycin caused a significant decrease in the LPS-stimulated IL-8 and GM-CSF release.. LPS upregulates release of IL-8 and GM-CSF from PBECs derived from stable lung allografts. Sub-microbicidal concentrations of azithromycin attenuate this and may, therefore, alleviate infection-driven neutrophilic airway inflammation and remodeling in the allograft airway.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchi; Bronchoalveolar Lavage Fluid; Bronchoscopy; Epithelial Cells; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Inflammation; Interleukin-8; Lipopolysaccharides; Lung Transplantation; Transplantation, Homologous

Clinical studies revealed that azithromycin reduces airway neutrophilia during chronic rejection after lung transplantation. Our aim was to investigate the possible effect of azithromycin on ischaemia-reperfusion injury. Azithromycin or water was administered to mice every other day during 2 weeks (n = 6/group). On the 14th day, the left lung was clamped to induce ischaemia (90 min). In two additional groups, animals underwent the same protocol, followed by 4 h of reperfusion. Two control groups were included with thoracotomy only. Inflammatory parameters and oxidative stress were measured in broncho-alveolar lavage of the left lung. Leukocytes, lymphocytes, neutrophils, 8-isoprostane and IL-1beta levels after ischaemia and reperfusion were significantly reduced in mice treated with azithromycin. There was a trend towards lower IL-6 and KC levels. A significant correlation was seen between 8-isoprostanes and neutrophils (Pearson r = 0.72; P = 0.0086), IL-6 (Pearson r = 0.84; P = 0.0006), KC (Pearson r = 0.88; P = 0.0002) and IL-1beta (Pearson r = 0.62; P = 0.0326). We conclude (i) that azithromycin reduces inflammation and oxidative stress in our IRI model, and (ii) that oxidative stress is correlated with the number of neutrophils and IL-6, KC and IL-1beta levels after ischaemia and reperfusion. Azithromycin should be further investigated as a novel drug to prevent lung ischaemia-reperfusion injury.

Topics: Animals; Azithromycin; Bronchoalveolar Lavage Fluid; Chemokines; Cytokines; Dinoprost; Female; Inflammation; Interleukin-1beta; Interleukin-6; Leukocyte Count; Lung; Mice; Neutrophils; Oxidative Stress; Reperfusion Injury

Serum amyloid A protein (SAA) is an acute phase protein, known to be a sensitive indicator of inflammation. We have characterized the time course of the SAA response and inflammatory reaction to silver nitrate injection s.c. in mice and studied the effects of dexamethasone and macrolide antibiotics. 2% Sterile silver nitrate solution was injected s.c. into female BALB/c mice and blood collected by capillary action from the tail vein of each mouse at different time points. Hematological variables were determined, albumin by spectrophotometry and SAA and cytokines by ELISA. Animals were treated with either a single i.p. dose of dexamethasone (5-30 mg/kg) 1 h after or daily oral doses of macrolide antibiotics for 3 days. SAA concentrations after silver nitrate injection peaked at 24 h, preceded by increases in serum IL-1 beta and IL-6, associated with decreases in blood leukocytes and local tissue inflammation. Single dexamethasone treatment and daily dosing for 3 days with azithromycin, clarithromycin and roxithromycin (20-80 mg/kg p.o.), but not erythromycin (100-150 mg/kg p.o.), inhibited the increase in SAA but with varying time courses. SAA, measured continuously, is a useful marker of sterile inflammation in mice and is differentially inhibited by macrolide antibiotics.

Topics: Acute-Phase Reaction; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Cell Count; Clarithromycin; Dexamethasone; Female; Inflammation; Interleukin-1beta; Interleukin-6; Leukocyte Count; Macrolides; Mice; Mice, Inbred BALB C; Muscle, Skeletal; Neutrophils; Platelet Count; Roxithromycin; Serum Amyloid A Protein; Silver Nitrate; Subcutaneous Fat

Topics: Anti-Bacterial Agents; Azithromycin; Blindness; Child, Preschool; Chronic Disease; Diagnosis, Differential; Female; Humans; Inflammation; Population Surveillance; Prevalence; Public Health; Trachoma; World Health Organization

Topics: Acute Disease; Angina, Unstable; Azithromycin; Chlamydophila Infections; Humans; Inflammation; Intercellular Adhesion Molecule-1; Myocardial Infarction; Survivors; Syndrome

Inflammation is a key pathogenic component of atherosclerosis; it also promotes thrombosis, a process underlying acute coronary events and stroke. Cells present in atherosclerotic plaque show abnormal tissue factor (TF) expression. Macrolides, in addition to their antimicrobial properties, have antiinflammatory effects that might help prevent atherothrombosis. The aim of this study was to determine the effect of an immunosuppressant macrolide, rapamycin (Sirolimus), on the expression of TF and its inhibitor (TFPI) by monocytic cells (human blood mononuclear and THP-1 cells) and human aortic smooth muscle cells, in comparison with FK-506 and azithromycin. In monocytic cells, rapamycin and FK-506 inhibited LPS-induced TF activity, antigen and mRNA expression through a transcriptional mechanism involving NF-kappaB. In smooth muscle cells, rapamycin and azithromycin had no effect on serum-induced TF expression, while FK-506 increased serum-induced TF protein and mRNA expression. TFPI levels in the culture supernatants of serum-stimulated smooth muscle cells were not modified by any of the three macrolides. Rapamycin slightly inhibits TFPI induction by LPS in monocytic cells. In addition to its recently established efficacy in the prevention of stent restenosis, the inhibitory effect of rapamycin on the TF pathway might have interesting therapeutic implications.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Aorta; Azithromycin; Cell Nucleus; Cell Survival; Cells, Cultured; Coagulants; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Inflammation; Leukocytes, Mononuclear; Lipopolysaccharides; Monocytes; Muscle, Smooth; Myocytes, Smooth Muscle; NF-kappa B; Plasmids; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sirolimus; Tacrolimus; Thromboplastin; Transcription, Genetic

Shiga toxin (Stx)-producing Escherichia coli (STEC) colonizes the human intestinal mucosa, produces Stx from phage, and causes the development of hemolytic-uremic syndrome via Stx-induced inflammatory cytokine production. Azithromycin exhibited strong in vitro activity against STEC without inducing Stx-converting phage, in marked contrast to norfloxacin. Azithromycin decreased the tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 production from Stx-treated human peripheral mononuclear cells or monocytes to a greater extent than did clarithromycin. In Stx-injected mice, azithromycin significantly suppressed Stx-induced TNF-alpha, IL-1beta, and IL-6 levels in serum and improved the outcome as assessed by survival rate. In the STEC oral infection experiment using immature mice immediately after weaning (weaned immature-mouse model), all mice died within 7 days postinfection. Azithromycin administration gave the mice 100% protection from killing, while ciprofloxacin administration gave them 67% protection. The data suggest that azithromycin (at least at higher concentrations) has a strong effect on Stx production by STEC and on the Stx-induced inflammatory host response and prevents death in mice. Azithromycin may have a beneficial effect on STEC-associated disease.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Bacteriophages; Cytokines; Dose-Response Relationship, Drug; Escherichia coli; Escherichia coli Infections; Humans; In Vitro Techniques; Inflammation; Male; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Monocytes; Shiga Toxin; Survival Analysis

The penetration of azithromycin into the blister fluids of six volunteers was analyzed after a 5-day regimen (total of 1.5 g). Differences in drug concentrations in a paper disk and serum and in the mass of azithromycin from inflammatory blister chamber leukocytes and noninflammatory blister chamber leukocytes were significant (P < 0.05).

Topics: Azithromycin; Blister; Female; Humans; Inflammation; Leukocyte Count; Male

The possibility of augmentation of azithromycin delivery to infection loci was evaluated by the use of Staphylococcus aureus thigh infection models with CD-1 mice. The intramuscular infections that developed were characterized by rapid growth of bacteria and induction of a localized oedema that was assessed gravimetrically. Microscopic examination of infected thighs showed massive infiltration of polymorphonuclear leucocytes (viable and degranulated), when compared to saline-injected thighs, from 24 to > or = 72 h after infection. Azithromycin concentrations were enhanced significantly (P < or = 0.02) in infected thigh tissues compared with contralateral non-infected tissues, and correlated with oedema from 24-72 h after challenge and dosing. The azithromycin levels in infected tissue after a 5 mg/kg dose were sufficient to cause a significant reduction in the number of cfu. If azithromycin administration was delayed until inflammation was more severe, the result was an even greater preferential concentration of azithromycin into the infected thigh. Preferential concentration of azithromycin was not observed when extensive oedema was produced by injection of histamine. However, this oedema was not associated with a significant influx of polymorphonuclear leucocytes. In comparative studies, macrolide antibiotics known to be concentrated in phagocytes, such as erythromycin, roxithromycin, and clarithromycin, were not concentrated preferentially in infected tissues under the experimental conditions used; tissue levels were above or at the in-vitro MIC level for < or = 24 h. The data indicate that delivery of biologically available azithromycin to infected tissues is enhanced by cellular inflammatory processes.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Erythromycin; Histamine; Inflammation; Male; Mice; Mice, Inbred Strains; Staphylococcal Infections; Staphylococcus aureus; Thigh

In the present studies the in vivo and in vitro effects of erythromycin A and azithromycin, a new type of macrolide (Fig. 2.), were investigated upon extracellular release of lysosomal enzymes, beta-glucuronidase (beta-Gluc) and beta-N-acetylglucosaminidase (beta-Glm) by using two experimental model systems: in vivo-adjuvant-induced arthritis in rats and in vitro- human polymorphonuclear leucocytes (PMNL) exposed to bovine serum albumin/anti-bovine serum albumin (BSA/anti-BSA), immune complex. Administrations of erythromycin A or azithromycin at doses of 5, 10 and 15 mg/kg into rats one day prior and 2, 4, 6, 8 and 10 days after a single subplantar injection of Freund's complete adjuvant significantly (p less than 0.01) inhibited extracellular release of lysosomal enzymes tested in the synovial fluid of injected left hind paw. These effects were dose-dependent. Further, erythromycin A and azithromycin at concentrations of 10(-7) M, 10(-6) M and 10(-5) M significantly (p less than 0.01) reduced excocytosis of both lysosomal enzymes, beta-Gluc and beta-Glm from human PMNL initiated by BSA/anti-BSA in a dose-related fashion. However, azithromycin was by far more effective (p less than 0.01) in decreasing extracellular release of beta-Gluc and beta-Glm either in the in vivo or in vitro experiments in comparison with erythromycin A. Appropriate control experiments excluded the possibilities that erythromycin A or azithromycin interfered with activities of lysosomal enzymes or with test reagents. Also, in no instances was there enhanced release of a cytoplasmic enzyme LDH.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylglucosaminidase; Animals; Arthritis, Experimental; Azithromycin; Erythromycin; Female; Glucuronidase; Humans; In Vitro Techniques; Inflammation; L-Lactate Dehydrogenase; Lysosomes; Male; Neutrophils; Rats; Rats, Inbred Strains