zithromax and Pseudomonas-Infections

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Anti-virulence strategies have not been evaluated for the prevention of bacterial infections. Prolonged colonization of intubated patients with Pseudomonas aeruginosa isolates producing high-levels of the quorum sensing (QS)-regulated virulence factor rhamnolipids has been associated with ventilator-associated pneumonia (VAP). In this pathogen, azithromycin reduces QS-regulated virulence. We aimed to assess whether azithromycin could prevent VAP in patients colonized by rhamnolipids producing isolates.. In a randomized, double-blind, multicenter trial, intubated colonized patients received either 300 mg/day azithromycin or placebo. Primary endpoint was the occurrence of P. aeruginosa VAP. We further identified those patients persistently colonized by isolates producing high-levels of rhamnolipids and therefore at the highest risk to develop VAP linked to this QS-dependent virulence factor.. Ninety-two patients were enrolled; 43 azithromycin-treated and 42 placebo patients were eligible for the per-protocol analysis. In the per-protocol population, the occurrence of P. aeruginosa VAP was reduced in the azithromycin group but without reaching statistical significance (4.7 vs. 14.3 % VAP, p = 0.156). QS-dependent virulence of colonizing isolates was similarly low in both study groups, and only five patients in each arm were persistently colonized by high-level rhamnolipids producing isolates. In this high-risk subgroup, the incidence of VAP was reduced fivefold in azithromycin versus placebo patients (1/5 vs. 5/5 VAP, p = 0.048).. There was a trend towards reduced incidence of VAP in colonized azithromycin-treated patients. In addition, azithromycin significantly prevented VAP in those patients at high risk of rhamnolipid-dependent VAP, suggesting that virulence inhibition is a promising anti-microbial strategy.

Topics: Anti-Bacterial Agents; Antibiotic Prophylaxis; Azithromycin; Double-Blind Method; Female; Glycolipids; Humans; Male; Middle Aged; Pilot Projects; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Pseudomonas Infections; Quorum Sensing; Virulence

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

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

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

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

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

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

With the rising development of bacterial resistance the search for new medical treatments beyond conventional antimicrobials has become a key aim of public health research. Possible innovative strategies include the inhibition of bacterial virulence. However, consideration must be given to the evolutionary and environmental consequences of such new interventions. Virulence and cooperative social behaviour of the bacterium Pseudomonas aeruginosa rely on the quorum-sensing (QS) controlled production of extracellular products (public goods). Hence QS is an attractive target for anti-virulence interventions. During colonization, non-cooperating (and hence less virulent) P. aeruginosa QS-mutants, benefiting from public goods provided by wild type isolates, naturally increase in frequency providing a relative protection from invasive infection. We hypothesized that inhibition of QS-mediated gene expression removes this growth advantage and selection of less virulent QS-mutants, and maintains the predominance of more virulent QS-wild type bacteria. We addressed this possibility in a placebo-controlled trial investigating the anti-QS properties of azithromycin, a macrolide antibiotic devoid of bactericidal activity on P. aeruginosa, but interfering with QS, in intubated patients colonized by P. aeruginosa. In the absence of azithromycin, non-cooperating (and hence less virulent) lasR (QS)-mutants increased in frequency over time. Azithromycin significantly reduced QS-gene expression measured directly in tracheal aspirates. Concomitantly the advantage of lasR-mutants was lost and virulent wild-type isolates predominated during azithromycin treatment. We confirmed these results in vitro with fitness and invasion experiments. Azithromycin reduced growth rate of the wild-type, but not of the lasR-mutant. Furthermore, the lasR-mutant efficiently invaded wild-type populations in the absence, but not in the presence of azithromycin. These in vivo and in vitro results demonstrate that anti-virulence interventions based on QS-blockade diminish natural selection towards reduced virulence and therefore may increase the prevalence of more virulent genotypes in the Hospital environment. More generally, the impact of intervention on the evolution of virulence of pathogenic bacteria should be assessed.

Topics: Anti-Bacterial Agents; Azithromycin; Critical Illness; Drug Resistance, Bacterial; Evolution, Molecular; Humans; Mutation; Placebos; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Quorum Sensing; Respiration, Artificial; Trachea; Virulence

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Development of new bacterial biofilm inhibitors as antibacterial synergists is an effective strategy to solve the resistance of

Topics: Animals; Anti-Bacterial Agents; Biofilms; Cell Line; Cell Survival; Colony Count, Microbial; Drug Resistance, Multiple, Bacterial; Drug Synergism; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Pyocyanine; Pyridines; Quinolones; Quorum Sensing; Zebrafish

Topics: Anti-Bacterial Agents; Bacterial Adhesion; Biofilms; Carbohydrates; Dipeptides; Glycosylation; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Quorum Sensing; Virulence Factors

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

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

Robust biofilms and the complex airway environment with thick sputum, local hypoxia and persistent inflammation induce the intractability of chronic pulmonary infections caused by Pseudomonas aeruginosa (P. aeruginosa). Herein, we proposed a type of antibiotic-adjuvant liposomes (NANO@PS-LPs), co-incorporating azithromycin (AZI), adjuvant (2-nitroimidazole derivative, 6-NIH) and biofilm dispersant (nitric oxide donor, DETA NONOate). NANO@PS-LPs possessing negatively-charged surface and good hydrophilicity could easily penetrate through the sputum layer, then disassembled triggered by overexpressed phospholipase A

Topics: Anti-Bacterial Agents; Azithromycin; Biofilms; Humans; Hypoxia; Lipopolysaccharides; Liposomes; Microbial Sensitivity Tests; Phospholipases; Pseudomonas aeruginosa; Pseudomonas Infections

To explore the clinical benefits of azithromycin in the treatment of Pseudomonas aeruginosa induced bronchiectasis and to evaluate its effect on MUC5AC. From April 2018 to June 2020, 160 patients with bronchiectasis due to Pseudomonas aeruginosa infection were selected. The patients were divided into a control groupand an azithromycin group. Statistics of patients' general clinical data, lung function indexes, sputum volume, oxidative stress level, Bhalla score before and after treatment; Western blot analysis of MUC5AC expression; RT-PCR analysis of TNF-α, IL-8, IL- 1β mRNA expression. The mRNA expression of TNF-α, IL-8 and IL-1β in the azithromycin group was lower than that in the control group (P<0.05). After treatment, the protein expression of MUC5AC in the azithromycin group was lower than that in the control group (P<0.05). The improvement rate in the azithromycin group was significantly higher than that in the control group (P<0.05). The azithromycin group had a lower lung infection rate than the control group (P<0.05). The azithromycin group had a lower dyspnea rate than the control group (P<0.05). Azithromycin treatment has certain clinical benefits for patients with bronchiectasis induced by Pseudomonas aeruginosa and inhibits the MUC5AC expression.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bronchiectasis; Dyspnea; Female; Humans; Interleukin-1beta; Interleukin-8; Male; Middle Aged; Mucin 5AC; Pseudomonas aeruginosa; Pseudomonas Infections; RNA, Messenger; Tumor Necrosis Factor-alpha

Topics: Acinetobacter Infections; Aged; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Azithromycin; Bacteremia; Candidemia; COVID-19 Drug Treatment; Enzyme Inhibitors; Female; Gram-Negative Bacterial Infections; Humans; Hydroxychloroquine; Italy; Klebsiella Infections; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Pneumonia, Ventilator-Associated; Protective Factors; Pseudomonas Infections; Respiration, Artificial; SARS-CoV-2; Staphylococcal Infections; Superinfection; Teicoplanin

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

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

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

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

Nanoparticles are becoming increasingly important against resistant superbugs including Pseudomonas aeruginosa infections.. Exploration of Azithromycin as an adjunctive therapy to Ciprofloxacin for treatment of P. aeruginosa infections. Also, preparation of Ciprofloxacin-Azithromycin nanoparticles on chitosan nanocarrier (Cipro-AZM-CS) and assessment of its antimicrobial effect in vitro and in vivo.. Detection of biofilm production and biofilm-specific antibiotic resistance ndvB and tssC1 genes was attempted. Minimal inhibitory concentration (MIC) and Minimum biofilm eradication concentration (MBEC) were done in vitro for assessment of P. aeruginosa planktonic and biofilm forms eradication, respectively. In In vivo study, Cipro-AZM-CS and free form were used to evaluate survival rate, wound contraction and bacterial load in mice after third degree burn.. All isolates were positive for biofilm production and ndvB and tssC1 genes. Majority of isolates (37, 74%) were extensively drug resistant. In the planktonic state, MIC values of Cipro-AZM free and CS forms were significantly lower than free Cipro MIC (P = 0.015 and P < 0.001 respectively). Also, Cipro-AZM free and CS MBEC values were significantly lower than that of free Cipro (P < 0.010 and P < 0.001 respectively). Furthermore, The MIC and MBEC values of free Cipro-AZM decreased significantly when challenged with Cipro-AZM-CS (P = 0.009 and P < 0.001 respectively). In vivo study combined free and Cipro-AZM-CS treated subgroups showed 100% mice survival with early resolution of infection and wound contraction (75%, 77.5% respectively) VS 45% for Cipro CS (P < 0.001).. Combined free and Cipro-AZM-CS showed promising results in vitro and in vivo overcoming high resistance of biofilm producing P. aeruginosa.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Biofilms; Burns; Ciprofloxacin; Drug Therapy, Combination; Mice; Microbial Sensitivity Tests; Nanomedicine; Pseudomonas aeruginosa; Pseudomonas Infections

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

Bronchiectasis is predominantly a neutrophilic inflammatory disease. There are no established therapies that directly target neutrophilic inflammation because little is understood of the underlying mechanisms leading to severe disease. Neutrophil extracellular trap (NET) formation is a method of host defence that has been implicated in multiple inflammatory diseases. We aimed to investigate the role of NETs in disease severity and treatment response in bronchiectasis.. In this observational study, we did a series of UK and international studies to investigate the role of NETs in disease severity and treatment response in bronchiectasis. First, we used liquid chromatography-tandem mass spectrometry to identify proteomic biomarkers associated with disease severity, defined using the bronchiectasis severity index, in patients with bronchiectasis (n=40) in Dundee, UK. Second, we validated these biomarkers in two cohorts of patients with bronchiectasis, the first comprising 175 patients from the TAYBRIDGE study in the UK and the second comprising 275 patients from the BRIDGE cohort study from centres in Italy, Spain, and UK, using an immunoassay to measure NETs. Third, we investigated whether pathogenic bacteria had a role in NET concentrations in patients with severe bronchiectasis. In a separate study, we enrolled patients with acute exacerbations of bronchiectasis (n=20) in Dundee, treated with intravenous antibiotics for 14 days and proteomics were used to identify proteins associated with treatment response. Findings from this cohort were validated in an independent cohort of patients who were admitted to the same hospital (n=20). Fourth, to assess the potential use of macrolides to reduce NETs in patients with bronchiectasis, we examined two studies of long-term macrolide treatment, one in patients with bronchiectasis (n=52 from the UK) in which patients were given 250 mg of azithromycin three times a week for a year, and a post-hoc analysis of the Australian AMAZES trial in patients with asthma (n=47) who were given 500 mg of azithromycin 3 times per week for a year.. Sputum proteomics identified that NET-associated proteins were the most abundant and were the proteins most strongly associated with disease severity. This finding was validated in two observational cohorts, in which sputum NETs were associated with bronchiectasis severity index, quality of life, future risk of hospital admission, and mortality. In a subgroup of 20 patients with acute exacerbations, clinical response to intravenous antibiotic treatment was associated with successfully reducing NETs in sputum. Patients with Pseudomonas aeruginosa infection had a lessened proteomic and clinical response to intravenous antibiotic treatment compared with those without Pseudomonas infections, but responded to macrolide therapy. Treatment with low dose azithromycin was associated with a significant reduction in NETs in sputum over 12 months in both bronchiectasis and asthma.. We identified NETs as a key marker of disease severity and treatment response in bronchiectasis. These data support the concept of targeting neutrophilic inflammation with existing and novel therapies.. Scottish Government, British Lung Foundation, and European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC).

Topics: Anti-Bacterial Agents; Azithromycin; Biomarkers; Bronchiectasis; Cohort Studies; Extracellular Traps; Humans; Macrolides; Proteomics; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Function Tests; Severity of Illness Index; Sputum

Bacterial biofilm is the complicated clinical issues, which usually results in bacterial resistance and reduce the therapeutic efficacy of antibiotics. Although micelles have been drawn attention in treatment of the biofilms, the micelles effectively permeate and retain in biofilms still facing a big challenge. In this study, we fabricated on-demand pH-sensitive surface charge-switchable azithromycin (AZM)-encapsulated micelles (denoted as AZM-SCSMs), aiming to act as therapeutic agent for treating Pseudomonas aeruginosa (P. aeruginosa) biofilms. The AZM-SCSMs was composed of poly(L-lactide)-polyetherimide-hyd-methoxy polyethylene glycol (PLA-PEI-hyd-mPEG). It was noteworthy that the pH-sensitive acylhydrazone bond could be cleaved in acidic biofilm microenvironment, releasing the secondary AZM-loaded cationic micelles based on PLA-PEI (AZM-SCMs) without destroying the micellar integrity, which could tailor drug-bacterium interaction using micelles through electrostatic attraction. The results proved that positively charged AZM-SCMs could facilitate the enhanced penetration and retention inside biofilms, improved binding affinity with bacterial membrane, and added drug internalization, thus characterized as potential anti-biofilm agent. The excellent in vivo therapeutic performance of AZM-SCSMs was confirmed by the targeting delivery to the infected tissue and reduced bacterial burden in the abscess-bearing mice model. This study not only developed a novel method for construction non-depolymerized pH-sensitive SCSMs, but also provided an effective means for the treatment of biofilm-related infections.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Biofilms; Cell Survival; Chlorocebus aethiops; Hydrogen-Ion Concentration; Male; Mice; Mice, Inbred BALB C; Micelles; Nanotechnology; Polyesters; Polyethylene Glycols; Polymers; Pseudomonas aeruginosa; Pseudomonas Infections; Vero Cells

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

Genetic studies have led to identification of an increasing number of monogenic primary immunodeficiency disorders. Monoallelic pathogenic gain-of-function (GOF) variants in NFKBIA, the gene encoding IκBα, result in an immunodeficiency disorder, typically accompanied by anhidrotic ectodermal dysplasia (EDA). So far, 14 patients with immunodeficiency due to NFKBIA GOF mutations have been reported. In this study we report three patients from the same family with immunodeficiency, presenting with recurrent respiratory tract infections, bronchiectasis and viral skin conditions due to a novel pathogenic NFKBIA variant (c.106 T > G, p.Ser36Ala), which results in reduced IκBα degradation. Immunological investigations revealed inadequate antibody responses against vaccine antigens, despite hypergammaglobulinemia. Interestingly, none of the studied patients displayed features of EDA. Therefore, missense NFKBIA variants substituting serine 36 of IκBα, differ from the rest of pathogenic GOF NFKBIA variants in that they cause combined immunodeficiency, even in the absence of EDA.

Topics: Adult; Arthritis, Juvenile; Azithromycin; Bronchiectasis; Cell Proliferation; Cells, Cultured; Child; Ectodermal Dysplasia; Gain of Function Mutation; Gentamicins; Humans; Immunologic Deficiency Syndromes; Leukocytes, Mononuclear; Male; Meningitis, Bacterial; Neisseria meningitidis; NF-KappaB Inhibitor alpha; Papillomaviridae; Pedigree; Pseudomonas aeruginosa; Pseudomonas Infections; Virus Diseases; Warts; Young Adult

We studied the effect of subbacteriostatic azithromycin concentrations on the formation of microbial biofilms by Pseudomonas aeruginosa strains that caused implant-associated infection of large joints. Azithromycin in subinhibitory for planktonic cells concentrations 0.01-0.02 μg/ml stimulated biofilm formation by both clinical and reference P. aeruginosa strains, while in concentrations of 1 μg/ml and higher completely inhibited the growth of both reference and clinical plankton P. aeruginosa strains, but stimulated biofilm formation. Increasing azithromycin concentration to 10 μg/ml led to inhibition of P. aeruginosa biofilm growth.

Topics: Anti-Bacterial Agents; Arthroplasty, Replacement; Azithromycin; Biofilms; Humans; Joints; Microbial Sensitivity Tests; Plankton; Pseudomonas aeruginosa; Pseudomonas Infections

Nowadays, the resistance of bacterial biofilms towards the available antibiotics is a severe problem. Therefore, many efforts were devoted to develop new formulations using nanotechnology. We have developed an inhalable microparticle formulation using spray-drying combining multiple drugs: an antibiotic (tobramycin, ciprofloxacin or azithromycin), N-acetylcysteine (NAC), and curcumin (Cur). The use of PLGA nanoparticles (NP) also allowed incorporating curcumin to facilitate spray drying and modify the release of some compounds. The aerosolizable microparticles formulations were characterized in terms of size, morphology, and aerodynamic properties. Biocompatibility when tested on macrophage-like cells was acceptable after 20 h exposure for concentrations up to at least 32 µg/mL. Antibacterial activity of free drugs versus drugs in the multiple drug formulations was evaluated on P. aeruginosa in the same range. When co-delivered the efficacy of tobramycin was enhanced compared to the free drug for the 1 µg/mL concentration. The combinations of azithromycin and ciprofloxacin with NAC and Cur did not show an improved antibacterial activity. Bacteria-triggered cytokine release was not inhibited by free antibiotics, except for TNF-α. In contrast, the application of NAC and the addition of curcumin-loaded PLGA NPs showed a higher potential to inhibit TNF-α, IL-8, and IL-1β release. Overall, the approach described here allows simultaneous delivery of antibacterial, mucolytic, and anti-inflammatory compounds in a single inhalable formulation and may therefore pave the way for a more efficient therapy of pulmonary infections.

Topics: Acetylcysteine; Administration, Inhalation; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Ciprofloxacin; Curcumin; Cytokines; Drug Carriers; Drug Combinations; Drug Compounding; Expectorants; Freeze Drying; Humans; Inflammation Mediators; Macrophages; Microbial Viability; Mucus; Nanoparticles; Permeability; Polylactic Acid-Polyglycolic Acid Copolymer; Pseudomonas aeruginosa; Pseudomonas Infections; THP-1 Cells; Tobramycin

Trans-translation is a ribosome rescue system that plays an important role in bacterial tolerance to environmental stresses. It is absent in animals, making it a potential treatment target. However, its role in antibiotic tolerance in Pseudomonas aeruginosa remains unknown.. The role and activity of trans-translation during antibiotic treatment were examined with a trans-translation-deficient strain and a genetically modified trans-translation component gene, respectively. In vitro assays and murine infection models were used to examine the effects of suppression of trans-translation.. We found that the trans-translation system plays an essential role in P. aeruginosa tolerance to azithromycin and multiple aminoglycoside antibiotics. We further demonstrated that gentamicin could suppress the azithromycin-induced activation of trans-translation. Compared with each antibiotic individually, gentamicin and azithromycin combined increased the killing efficacy against planktonic and biofilm-associated P. aeruginosa cells, including a reference strain PA14 and its isogenic carbapenem-resistance oprD mutant, the mucoid strain FRD1, and multiple clinical isolates. Furthermore, the gentamicin-azithromycin resulted in improved bacterial clearance in murine acute pneumonia, biofilm implant, and cutaneous abscess infection models.. Combination treatment with gentamicin and azithromycin is a promising strategy in combating P. aeruginosa infections.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Disease Models, Animal; Drug Therapy, Combination; Drug Tolerance; Female; Gentamicins; Mice, Inbred BALB C; Microbial Viability; Pneumonia, Bacterial; Protein Biosynthesis; Pseudomonas aeruginosa; Pseudomonas Infections; Treatment Outcome

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

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

Long-term use of nebulized or oral antibiotics is common in the treatment of cystic fibrosis and non-cystic fibrosis bronchiectasis. To date, however, few studies have focused on the use of nebulized antibiotics in COPD patients. The aims of this study are: to establish whether a combination of nebulized colistin plus continuous cyclic azithromycin in severe COPD patients with chronic bronchial infection due to. A retrospective cohort was created for the analysis of patients with severe COPD and chronic bronchial infection due to. We analyzed 32 severe COPD patients who received nebulized colistin for at least three months (median 17 months [IQR 7-24]). All patients but one received combination therapy with continuous cyclic azithromycin (median 24 months [IQR 11-30]). A significant reduction in the number of ECOPD from baseline of 38.3% at two years of follow-up was observed, with a clear decrease in. In patients with severe COPD and chronic bronchial infection due to

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Anti-Bacterial Agents; Azithromycin; Bronchi; Colistin; Disease Progression; Drug Therapy, Combination; Female; Humans; Male; Nebulizers and Vaporizers; Pseudomonas Infections; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Infections; Retrospective Studies; Severity of Illness Index; Sputum; Time Factors; Treatment Outcome

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

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

Topics: Anti-Bacterial Agents; Azithromycin; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Quorum Sensing; Ribosomes; Virulence Factors

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

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

Topics: Aged; Anti-Bacterial Agents; Azithromycin; Campylobacter Infections; Coinfection; Colitis, Ulcerative; Feces; Female; Fever; Humans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas Infections; Sigmoidoscopy; Treatment Outcome

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

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

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

Over the past several decades, the frequency of antibacterial resistance in hospitals, including multidrug resistance (MDR) and its association with serious infectious diseases, has increased at alarming rates. Pseudomonas aeruginosa is a leading cause of nosocomial infections, and resistance to virtually all approved antibacterial agents is emerging in this pathogen. To address the need for new agents to treat MDR P. aeruginosa, we focused on inhibiting the first committed step in the biosynthesis of lipid A, the deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by the enzyme LpxC. We approached this through the design, synthesis, and biological evaluation of novel hydroxamic acid LpxC inhibitors, exemplified by 1, where cytotoxicity against mammalian cell lines was reduced, solubility and plasma-protein binding were improved while retaining potent anti-pseudomonal activity in vitro and in vivo.

Topics: Amidohydrolases; Animals; Anti-Bacterial Agents; Chemistry Techniques, Synthetic; Crystallography, X-Ray; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial; Enzyme Inhibitors; Female; Hep G2 Cells; Humans; K562 Cells; Mice, Inbred BALB C; Microbial Sensitivity Tests; Molecular Docking Simulation; Pseudomonas aeruginosa; Pseudomonas Infections; Structure-Activity Relationship

Macrolides have been reported to exert a variety of effects on both host immunomodulation and repression of bacterial pathogenicity. In this study, we report that the 3',5'-cyclic diguanylic acid (c-di-GMP) signaling system, which regulates virulence in Pseudomonas aeruginosa, is affected by the macrolide azithromycin. Using DNA microarray analysis, we selected a gene encoding PA2567 related to c-di-GMP metabolism that was significantly affected by azithromycin treatment. Expression of the PA2567 gene was significantly repressed by azithromycin in a time- and dose-dependent manner, whereas no difference in PA2567 gene expression was observed in the absence of azithromycin. In-frame deletion of the PA2567 gene affected both virulence factors and the quorum-sensing system, and significantly decreased total bacteria in a mouse pneumonia model compared to the wild-type strain (P < 0.05). These results suggest that macrolides possess the ability to modulate c-di-GMP intracellular signaling in P. aeruginosa.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Bacterial Proteins; Colony Count, Microbial; Cyclic GMP; Disease Models, Animal; Female; Mice; Mice, Inbred C57BL; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Signal Transduction; Virulence Factors

Macrolides antibiotics have been effectively used in many chronic diseases, especially with

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Bronchiectasis; Cells, Cultured; Humans; Inflammasomes; Macrolides; Macrophages; Mice; Mice, Inbred C57BL; Pseudomonas aeruginosa; Pseudomonas Infections

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

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

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

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

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

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

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

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

Infection caused by ureteral stent indwelling is one of the most difficult medical problems, since once bacteria reside in biofilms they are extremely resistant to antibiotics as well as to the host immune defences. In this study we assessed the in vitro and in vivo efficacy of azithromycin and ceftazidime in preventing ureteral stent infection by Pseudomonas aeruginosa.. The susceptibility testing with adherent bacteria showed that the biofilm was strongly inhibited by azithromycin treatment, ceftazidime against adherent bacteria in the presence of azithromycin showed the minimum inhibitory concentrations (MICs) and minimum bacteriocidal concentrations (MBCs) dramatically lower than those obtained in the absence of azithromycin. Moreover, ceftazidime plus azithromycin reduced twitching motility and production of rhamnolipid. For the single-treatment groups, in vivo intravenous injection of ceftazidime showed the highest inhibitory effect on bacterial load. Azithromycin prophylactic injection combined with ceftazidime showed increased inhibitory effect on bacterial load than that of each single antibiotic.. Combination of azithromycin and ceftazidime effectively prevent the formation of biofilm and reduced bacteria load of Pseudomonas aeruginosa compared to separate treatment of either of these two antibiotics. This combined treatment option have the potential to contribute to the success of Pseudomonas biofilm elimination in the clinical environment.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Biofilms; Ceftazidime; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Humans; Microbial Sensitivity Tests; Prosthesis-Related Infections; Pseudomonas aeruginosa; Pseudomonas Infections; Rats; Rats, Wistar; Stents

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

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

Biofilm formation is becoming a predominant feature in nosocomial infections. Since biofilms are increasingly resistant to antibiotics, making monotherapy ineffective, combination therapy appears to be relevant for their eradication. This study assessed the potential of azithromycin (AZM) and ciprofloxacin (CIP) alone and in combination in vitro and in a mouse model of urinary tract infection (UTI) induced with biofilm cells of Pseudomonas aeruginosa. In vitro antibacterial and antibiofilm activities of antibiotics alone and in combination were assessed using the fractional inhibitory concentration index (FICI), time-kill analysis and confocal laser scanning microscopy (CLSM). In vivo efficacy was evaluated in a UTI model by quantitation of bacterial burden in kidney and bladder tissue, renal histopathology, pathology index factors (MDA and NO), and pro-inflammatory (MIP-2 and IL-6) and anti-inflammatory (IL-10) cytokines. MICs of AZM and CIP for strain PAO1 were 256 and 0.5 μg/mL, respectively; MBECs were 4096 and 1024 μg/mL. Synergistic interaction was observed between AZM and CIP both against planktonic and biofilm bacteria (FICI<0.5). The combination was also able to inhibit biofilm formation (at MIC levels) as observed with CLSM. Oral therapy with AZM (500 mg/kg) and CIP (30 mg/kg) combination in mice for 4 days showed accelerated clearance of bacteria from kidney and bladder tissue, improved renal histopathology, decreased levels of MDA and NO, significant decline in MIP-2 and IL-6, and increased IL-10 in the kidney (P<0.0001). We conclude that AZM+CIP therapy holds promise against biofilm-associated UTIs as it confers antibacterial, immunomodulatory and anti-inflammatory effects.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Bacterial Load; Biofilms; Ciprofloxacin; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Female; Histocytochemistry; Kidney; Mice; Microbial Sensitivity Tests; Microbial Viability; Microscopy, Confocal; Pseudomonas aeruginosa; Pseudomonas Infections; Treatment Outcome; Urinary Bladder; Urinary Tract Infections

In microbiology, changes in specialized metabolite production (cell-to-cell signaling metabolites, virulence factors, and natural products) are measured using phenotypic assays. However, advances in mass spectrometry-based techniques including imaging mass spectrometry (IMS) now allow researchers to directly visualize the production of specialized metabolites from microbial colony biofilms. In this study, a combination of IMS and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to visualize the effect of the macrolide antibiotic azithromycin (AZM) on colony biofilms of Pseudomonas aeruginosa. Although previous research suggested that AZM may inhibit cell-to-cell signaling of P. aeruginosa and thereby reduce pathogenicity, we observed no clear decrease in specialized metabolite production.

Topics: Anti-Bacterial Agents; Azithromycin; Biofilms; Chromatography, Liquid; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tandem Mass Spectrometry

Chronic inflammation of the airways is a central component in lung diseases and is frequently associated with bacterial infections. Monitoring the pro-inflammatory capability of bacterial virulence factors in vivo is challenging and usually requires invasive methods.. Lung inflammation was induced using the culture supernatants from two Pseudomonas aeruginosa clinical strains, VR1 and VR2, isolated from patients affected by cystic fibrosis and showing different phenotypes in terms of motility, colony characteristics and biofilm production as well as pyoverdine and pyocyanine release. More interesting, the strains differ also for the presence in supernatants of metalloproteases, a family of virulence factors with known pro-inflammatory activity. We have evaluated the benefit of using a mouse model, transiently expressing the luciferase reporter gene under the control of an heterologous IL-8 bovine promoter, to detect and monitoring lung inflammation.. In vivo imaging indicated that VR1 strain, releasing in its culture supernatant metalloproteases and other virulence factors, induced lung inflammation while the VR2 strain presented with a severely reduced pro-inflammatory activity. The bioluminescence signal was detectable from 4 to 48 h after supernatant instillation. The animal model was also used to test the anti-inflammatory activity of azithromycin (AZM), an antibiotic with demonstrated inhibitory effect on the synthesis of bacterial exoproducts. The inflammation signal in mice was in fact significantly reduced when bacteria grew in the presence of a sub-lethal dose of AZM causing inhibition of the synthesis of metalloproteases and other bacterial elements. The in vivo data were further supported by quantification of immune cells and cytokine expression in mouse broncho-alveolar lavage samples.. This experimental animal model is based on the transient transduction of the bovine IL-8 promoter, a gene representing a major player during inflammation, essential for leukocytes recruitment to the inflamed tissue. It appears to be an appropriate molecular read-out for monitoring the activation of inflammatory pathways caused by bacterial virulence factors. The data presented indicate that the model is suitable to functionally monitor in real time the lung inflammatory response facilitating the identification of bacterial factors with pro-inflammatory activity and the evaluation of the anti-inflammatory activity of old and new molecules for therapeutic use.

Topics: Animals; Azithromycin; Bronchoalveolar Lavage Fluid; Cattle; Cytokines; Diagnostic Imaging; Female; Humans; Interleukin-8; Mice, Inbred BALB C; Mice, Transgenic; Peptide Hydrolases; Phenotype; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Virulence Factors

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

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

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

Cutaneous thermal injuries (i.e., burns) remain a common form of debilitating trauma, and outcomes are often worsened by wound infection with environmental bacteria, chiefly Pseudomonas aeruginosa.. We tested the effects of early administration of a single dose of azithromycin, with or without subsequent antipseudomonal antibiotics, in a mouse model of standardized thermal injury infected with P aeruginosa via both wound site and systemic infection. We also tested the antimicrobial effects of these antibiotics alone or combined in comparative biofilm and planktonic cultures in vitro.. In our model, early azithromycin administration significantly reduced wound and systemic infection without altering wound site or circulating neutrophil activity. The antimicrobial effect of azithromycin was additive with ciprofloxacin but significantly reduced the antimicrobial effect of tobramycin. This pattern was reproduced in biofilm cultures and not observed in planktonic cultures of P aeruginosa.. These data suggest that early administration of azithromycin following burn-related trauma and infection may reduce P aeruginosa infection and potential interactions with other antibiotics should be considered when designing future studies.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Burns; Ciprofloxacin; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Male; Mice; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin; Treatment Outcome; Wound Infection

Topics: Azithromycin; Female; Glycolipids; Humans; Male; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Pseudomonas Infections

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

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

Topics: Azithromycin; Clarithromycin; Female; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections

The prognosis of patients with chronic respiratory tract infections, especially diffuse panbronchiolitis, is remarkably improved by long-term administration of low-dose macrolides. However, in some cases, patients are refractory to macrolide treatment and show a low or no response; therefore, new treatment strategies are required. Here we present a patient refractory to either single low-dose clarithromycin or azithromycin but responded remarkably to the combination usage of both macrolides.

Topics: Anti-Bacterial Agents; Azithromycin; Clarithromycin; Drug Therapy, Combination; Female; Humans; Immunologic Factors; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Treatment Outcome

Pseudomonas aeruginosa, an opportunistic pathogen, is the third most common pathogen associated with nosocomial urinary tract infections (UTIs). The virulence of this organism is due to its ability to produce quorum-sensing (QS) signal molecules and form biofilms. These biofilms are usually resistant to conventional antibiotics and host immune responses. Recently, beneficial effects of macrolides, especially azithromycin (AZM), have been shown in patients suffering from chronic infections caused by P. aeruginosa. These were due to anti-inflammatory and modulatory effects of AZM on the expression of virulence factors of this pathogen. The present study was designed to evaluate the potential of AZM to inhibit QS signal molecules and its ability to attenuate the virulence of P. aeruginosa in an experimental UTI model. Sub-MIC concentrations of AZM significantly inhibited the production of QS signals, swimming, swarming and twitching motilities, and biofilm formation in vitro. The therapeutic evaluation of AZM in this experimental UTI model showed complete clearance of the organisms from the mouse kidneys. The results of this study highlight the potential effectiveness of AZM in attenuating the virulence of P. aeruginosa in a UTI model.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Biofilms; Colony Count, Microbial; Disease Models, Animal; Female; Histocytochemistry; Humans; Kidney; Locomotion; Mice; Microbial Sensitivity Tests; Microscopy; Pseudomonas aeruginosa; Pseudomonas Infections; Quorum Sensing; Treatment Outcome; Urinary Tract Infections

Infection with mucoid strains of Pseudomonas aeruginosa in chronic inflammatory diseases of the airway is difficult to eradicate and can cause excessive inflammation. The roles of alternatively activated and regulatory subsets of macrophages in this pathophysiological process are not well characterized. We previously demonstrated that azithromycin induces an alternatively activated macrophage-like phenotype in vitro. In the present study, we tested whether azithromycin affects the macrophage activation status and migration in the lungs of P. aeruginosa-infected mice. C57BL/6 mice received daily doses of oral azithromycin and were infected intratracheally with a mucoid strain of P. aeruginosa. The properties of macrophage activation, immune cell infiltration, and markers of pulmonary inflammation in the lung interstitial and alveolar compartments were evaluated postinfection. Markers of alternative macrophage activation were induced by azithromycin treatment, including the surface expression of the mannose receptor, the upregulation of arginase 1, and a decrease in the production of proinflammatory cytokines. Additionally, azithromycin increased the number of CD11b(+) monocytes and CD4(+) T cells that infiltrated the alveolar compartment. A predominant subset of CD11b(+) cells was Gr-1 positive (Gr-1(+)), indicative of a subset of cells that has been shown to be immunoregulatory. These differences corresponded to decreases in neutrophil influx into the lung parenchyma and alteration of the characteristics of peribronchiolar inflammation without any change in the clearance of the organism. These results suggest that the immunomodulatory effects of azithromycin are associated with the induction of alternative and regulatory macrophage activation characteristics and alteration of cellular compartmentalization during infection.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; CD11b Antigen; CD11c Antigen; CD4-Positive T-Lymphocytes; Cytokines; Lung; Macrophage Activation; Mice; Mice, Inbred C57BL; Monocytes; Phenotype; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections

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

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

Previous studies have suggested that azithromycin improves lung function in lung transplant recipients with bronchiolitis obliterans syndrome (BOS). However, these studies did not include a non-treated BOS control cohort or perform survival analysis. This study was undertaken to estimate the effect of azithromycin treatment on survival in lung transplant recipients with BOS.. We conducted a retrospective cohort study of consecutive lung transplant recipients who developed BOS between 1999 and 2007. An association between azithromycin treatment and death was assessed using univariate and multivariate time-dependent Cox regression analysis.. Of the 178 recipients who developed BOS in our study, 78 did so after 2003 and were treated with azithromycin. The azithromycin-treated and untreated cohorts had similar baseline characteristics. Univariate analysis demonstrated that azithromycin treatment was associated with a survival advantage and this beneficial treatment effect was more pronounced when treatment was initiated during BOS Stage 1. Multivariate analysis demonstrated azithromycin treatment during BOS Stage 1 (adjusted hazard ratio = 0.23, p = 0.01) and absolute forced expiratory volume in 1 second (FEV(1)) at the time of BOS Stage 1 (adjusted hazard ratio = 0.52, p = 0.003) were both associated with a decreased risk of death.. In lung transplant recipients with BOS Stage 1, azithromycin treatment initiated before BOS Stage 2 was independently associated with a significant reduction in the risk of death. This finding supports the need for a randomized, controlled trial to confirm the impact of azithromycin on survival in lung transplant recipients.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Cause of Death; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Lung Transplantation; Male; Middle Aged; Opportunistic Infections; Postoperative Complications; Proportional Hazards Models; Pseudomonas Infections; Retrospective Studies; Risk Factors; Survival Analysis

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

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

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

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

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

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

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

Effects of hyperoxia on lethality in mice with Pseudomonas aeruginosa pneumonia were defined, and protective roles of macrolides were examined both in vitro and in vivo. Sub-lethal hyperoxia accelerated lethality of mice with P. aeruginosa pneumonia. Bacterial number was not different in the lungs, but higher in the liver of mice in hyperoxic conditions. Filter-sterilized culture supernatants of bacteria induced loss of viability of alveolar epithelial cells, which was exaggerated in hyperoxia. Metalloprotease blocking by inhibitor or gene-disruption in bacteria resulted in partial reduction of cytotoxic activity in culture supernatants. Co-culture of bacteria with sub-inhibitory concentrations of macrolides, such as azithromycin, reduced cytotoxic activity in the culture supernatants. Azithromycin provided significant survival benefit in hyperoxia-pneumonia model, which was associated with suppression of bacterial dissemination to extra-pulmonary organs. These results suggest that hyperoxia serves as an important cofactor for bacterial dissemination and lethality of P. aeruginosa pneumonia. Our data identify the potential of macrolides to protect individuals with P. aeruginosa pneumonia in the setting of hyperoxia.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Caspase 3; Cell Line; Cell Survival; Female; Gene Deletion; Histones; Humans; Hyperoxia; Liver; Lung; Macrolides; Mice; Mice, Inbred BALB C; Oxygen; Pneumonia, Bacterial; Protease Inhibitors; Pseudomonas aeruginosa; Pseudomonas Infections; Virulence Factors

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

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

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

Macrolide antibiotics modulate the quorum-sensing system of Pseudomonas aeruginosa. We tested the effect of macrolide antibiotics on the cell density-dependent expression of the MexAB-OprM efflux pump and found that 1.0 mug/ml (MIC/6.25) of azithromycin suppressed the expression of MexAB-OprM by about 70%, with the result that the cells became two- to fourfold more susceptible to antibiotics such as aztreonam, tetracycline, carbenicillin, chloramphenicol, and novobiocin.

Topics: Anti-Bacterial Agents; Azithromycin; Bacterial Outer Membrane Proteins; Down-Regulation; Humans; Macrolides; Membrane Transport Proteins; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Quorum Sensing

During infection, Pseudomonas aeruginosa employs bacterial communication (quorum sensing [QS]) to coordinate the expression of tissue-damaging factors. QS-controlled gene expression plays a pivotal role in the virulence of P. aeruginosa, and QS-deficient mutants cause less severe infections in animal infection models. Treatment of cystic fibrosis (CF) patients chronically infected with P. aeruginosa with the macrolide antibiotic azithromycin (AZM) has been demonstrated to improve the clinical outcome. Several studies indicate that AZM may accomplish its beneficial action in CF patients by impeding QS, thereby reducing the pathogenicity of P. aeruginosa. This led us to investigate whether QS inhibition is a common feature of antibiotics. We present the results of a screening of 12 antibiotics for their QS-inhibitory activities using a previously described QS inhibitor selector 1 strain. Three of the antibiotics tested, AZM, ceftazidime (CFT), and ciprofloxacin (CPR), were very active in the assay and were further examined for their effects on QS-regulated virulence factor production in P. aeruginosa. The effects of the three antibiotics administered at subinhibitory concentrations were investigated by use of DNA microarrays. Consistent results from the virulence factor assays, reverse transcription-PCR, and the DNA microarrays support the finding that AZM, CFT, and CPR decrease the expression of a range of QS-regulated virulence factors. The data suggest that the underlying mechanism may be mediated by changes in membrane permeability, thereby influencing the flux of N-3-oxo-dodecanoyl-L-homoserine lactone.

Topics: Anti-Bacterial Agents; Azithromycin; Base Sequence; Ceftazidime; Ciprofloxacin; DNA Primers; DNA, Bacterial; Gene Expression; Genes, Bacterial; Humans; Oligonucleotide Array Sequence Analysis; Opportunistic Infections; Polymerase Chain Reaction; Pseudomonas aeruginosa; Pseudomonas Infections; Quorum Sensing; Virulence

The consequences of O-acetylated alginate-producing Pseudomonas aeruginosa biofilms in the lungs of chronically infected cystic fibrosis (CF) patients are tolerance to both antibiotic treatments and effects on the innate and the adaptive defense mechanisms. In clinical trials, azithromycin (AZM) has been shown to improve the lung function of CF patients. The present study was conducted in accordance with previous in vitro studies suggesting that the effect of AZM may be the inhibition of alginate production, blockage of quorum sensing (QS), and increased sensitivity to hydrogen peroxide and the complement system. Moreover, we show that AZM may affect the polymerization of P. aeruginosa alginate by the incomplete precipitation of polymerized alginate and high levels of readily dialyzable uronic acids. In addition, we find that mucoid bacteria in the stationary growth phase became sensitive to AZM, whereas cells in the exponential phase did not. Interestingly, AZM-treated P. aeruginosa lasI mutants appeared to be particularly resistant to serum, whereas bacteria with a functional QS system did not. We show in a CF mouse model of chronic P. aeruginosa lung infection that AZM treatment results in the suppression of QS-regulated virulence factors, significantly improves the clearance of P. aeruginosa alginate biofilms, and reduces the severity of the lung pathology compared to that in control mice. We conclude that AZM attenuates the virulence of P. aeruginosa, impairs its ability to form fully polymerized alginate biofilms, and increases its sensitivity to complement and stationary-phase killing, which may explain the clinical efficacy of AZM.

Topics: Alginates; Animals; Anti-Bacterial Agents; Anti-Infective Agents, Local; Azithromycin; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Female; Humans; Hydrogen Peroxide; Lung; Lung Diseases; Male; Mice; Mice, Knockout; Pseudomonas aeruginosa; Pseudomonas Infections; Quorum Sensing; Virulence Factors

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

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

Topics: Anti-Bacterial Agents; Azithromycin; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas Infections; Serum Bactericidal Test

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

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

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

Topics: Anti-Infective Agents; Azithromycin; Bronchiectasis; Female; Humans; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Time Factors

Longterm macrolide therapy has been reported to be effective in treating chronic lower respiratory tract infections (CLRTIs). In this context, erythromycin and clarithromycin are usually used for this purpose. However, refractory cases are occasionally encountered, thereby indicating a major problem pending. In the present study, we administered azithromycin to three patients with CLRTIs whose clinical course had been unsatisfactory with longterm therapy of either erythromycin or clarithromycin. Following longterm therapy with azithromycin, both the incidence of acute exacerbations and the sputum volume were decreased. A significant change in the sputum flora was observed, without obvious side effects; however, no improvement was evidenced in the findings on flow volume curve tests and arterial blood gas analysis. In advanced disease, longterm azithromycin therapy may be as effective as that with erythromycin or clarithromycin; in our view, however, its efficacy may be limited, and large-scale clinical trials are required to determine the most suitable macrolide for the treatment of CLRTIs.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Chronic Disease; Diagnosis, Differential; Drug Administration Schedule; Fatal Outcome; Female; Humans; Male; Middle Aged; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections

Macrolides exert their effects on the host by modulation of immune responses. In this study, we assessed the therapeutic efficacy of azithromycin in a murine model of mucoid Pseudomonas aeruginosa endobronchial infection. The clearance of Pseudomonas from the airway of mice treated with the macrolide azithromycin was not different than untreated mice challenged with Pseudomonas beads. However, the azithromycin-treated mice showed a remarkable reduction in lung cellular infiltrate in response to Pseudomonas beads, as compared with untreated mice. This effect was associated with significant decreases in lung levels of tumor necrosis factor-alpha and keratinocyte-derived chemokine in azithromycin-treated mice compared with untreated mice. Furthermore, there was a significant reduction in the response of both mouse and human neutrophils to chemokine-dependent and -independent chemoattractants when studied in vitro. Inhibition of chemotaxis correlated with azithromycin-mediated inhibition of extracellular signal-regulated kinase-1 and -2 activation. This study indicates that the azithromycin treatment in vivo results in significant reduction in airway-specific inflammation, which occurs in part by inhibition of neutrophil recruitment to the lung through reduction in proinflammatory cytokine expression and inhibition of neutrophil migration via the extracellular signal-regulated kinase-1 and -2 signal transduction pathway.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Bronchial Diseases; Chemotactic Factors; Chemotaxis, Leukocyte; Cytokines; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Neutrophil Infiltration; Phosphatidylinositol 3-Kinases; Pseudomonas Infections

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

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

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

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

In this case, a 30-year-old man had been treated for chronic sinusitis and bronchiectasis since 2000, and presented at our outpatient clinic in May 2001 with chief complaints of massive yellow sputum expectoration and dyspnea. After he was admitted by our hospital, Pseudomonas aeruginosa bacteria were isolated at the rate of 10(8)/ml from his sputum culture. In electron-microscopic observation, the cilia of the bronchial epithelium were found to lack dynein arms. Semen examination revealed decreased sperm motility. Thus, the following diagnosis was made: diffuse bronchiectasis associated with the immotile-dyskinetic cilia syndrome, complicated with a P. aeruginosa infection. After the airway infection was ameliorated, 40 mg/day of clenbuterol hydrochloride was administered in combination with 250 mg of azithromycin, which was given twice a week, and which led to a markedly decreased frequency of exacerbation of airway infection. Moreover, chest CT scanning and respiratory function testing also indicated improvements. It was hypothesized that the decreased cilia motility due to P. aeruginosa-produced pyocyanin would be ameliorated with a b2 stimulant, and the inhibitory effect of a macrolide on the P. aeruginosa biofilm and production of pyocyanin would also be involved in the improvement of this case.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bronchodilator Agents; Ciliary Motility Disorders; Clenbuterol; Drug Therapy, Combination; Humans; Male; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Aged; Anti-Bacterial Agents; Azithromycin; Bronchiolitis; Female; Humans; Male; Middle Aged; Pseudomonas Infections; Treatment Outcome

Little information exists on risk factors for Pseudomonas aeruginosa infection in persons with HIV. We assessed the incidence and factors associated with P aeruginosa among persons with HIV enrolled in a large observational cohort study in Los Angeles.. Data were analyzed from 4825 persons aged > or =13 years with HIV infection enrolled from 4 outpatient facilities from 1990 to 1998. The association between P aeruginosa infection and demographic, risk behavior, and clinical factors was assessed.. P aeruginosa was diagnosed in 72 (1.5%) patients representing a crude incidence rate of 0.74 per 100 person-years. The most frequent site of infection was pulmonary (47%). In multivariate analysis, prior hospitalization (adjusted rate ratio = 7.9, 95% CI, 3.8-16.2), and both dapsone (adjusted rate ratio = 4.0, 95% CI, 2.2-7.4) and trimethoprim-sulfamethoxazole (adjusted rate ratio = 2.5, 95% CI, 1.2-5.3) use were independently associated with higher rates of infection. Increasing days of inpatient stay (P <.01) and decreasing CD4(+) counts (P <.01) were strongly associated with P aeruginosa. Azithromycin use decreased the risk of infection by nearly 70%.. Although the overall observed incidence of P aeruginosa was low, hospital exposure, declining CD4(+) levels, and the use of dapsone or trimethoprim-sulfamethoxazole increased the risk of P aeruginosa disease, and azithromycin use was protective in this population. These findings may assist in the early recognition and diagnosis of persons likely to be at increased risk of P aeruginosa infection.

Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Anti-Bacterial Agents; Azithromycin; CD4 Lymphocyte Count; Cohort Studies; Cross Infection; Dapsone; Female; Health Behavior; Hospitalization; Humans; Incidence; Infection Control; Length of Stay; Los Angeles; Male; Middle Aged; Multivariate Analysis; Pseudomonas aeruginosa; Pseudomonas Infections; Risk Factors; Risk-Taking; Trimethoprim, Sulfamethoxazole Drug Combination

While a time-kill methodology noted no appreciable improvement in bactericidal activity with the addition of azithromycin (AZM) to a ceftazidime (CAZ) regimen, data from the murine pneumonia model showed that the addition of AZM significantly improved survival compared to treatment with CAZ alone. These data suggest that AZM might be a useful adjunctive therapy in the management of pneumonia resulting from mucoid isolates of Pseudomonas aeruginosa.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Ceftazidime; Cephalosporins; Colony Count, Microbial; Drug Therapy, Combination; Humans; Mice; Pneumonia, Bacterial; Pseudomonas Infections; Survival Analysis; Time Factors; Urinary Tract Infections

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

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

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

The ability of three macrolide antibiotics (erythromycin, clarithromycin and azithromycin) to inhibit the expression of several pathogenicity traits of Pseudomonas aeruginosa at concentrations that do not affect the rate of growth of this microorganism was investigated. Sub-MICs of azithromycin manifested the broadest spectrum of action and strongly suppressed the synthesis of elastase, proteases, lecithinase and DNase. Clarithromycin and erythromycin were far less effective. Gelatinase was reduced almost to the same level by the three antibiotics, while haemolysins and lipase were only marginally affected. Loss of motility was a strain and drug-dependent event, but all the macrolides tested shared the ability to induce this effect. However, only azithromycin totally suppressed synthesis of pyocyanin in all isolates. These results indicate that newer macrolides and especially axithromycin are endowed with a remarkable ability to inhibit in vitro the expression of a number of physiological processes that are considered more essential than replication in the pathogenesis of P. aeruginosa. Since erythromycin sub-MICs have already been shown to exert beneficial effects in clinical practice, our data, pointing to a much higher potency of azithromycin, suggest its use in future studies.

Topics: Anti-Bacterial Agents; Azithromycin; Cell Movement; Clarithromycin; Erythromycin; Hemolysin Proteins; Humans; Lipase; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Pyocyanine; Virulence