These data provide evidence that azithromycin affects the inflammatory process at the level of the macrophage and shifts macrophage polarization towards the alternatively activated phenotype. This recently defined M2 phenotype has been described in conditions in which pulmonary inflammation and fibrosis are major determinants of clinical outcome, but the concept of antibiotics altering macrophage phenotype has not yet been critically evaluated.

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

Azithromycin is effective at controlling exaggerated inflammation and slowing the long-term decline of lung function in patients with cystic fibrosis. We previously demonstrated that the drug shifts macrophage polarization toward an alternative, antiinflammatory phenotype. In this study we investigated the immunomodulatory mechanism of azithromycin through its alteration of signaling via the NF-kB and STAT1 pathways. J774 murine macrophages were plated, polarized (with IFN-g, IL-4/-13, or with azithromycin plus IFN-g) and stimulated with LPS. The effect of azithromycin on NF-kB and STAT1 signaling mediators was assessed by Western blot, homogeneous time-resolved fluorescence assay, nuclear translocation assay, and immunofluorescence. The drug's effect on gene and protein expression of arginase was evaluated as a marker of alternative macrophage activation. Azithromycin blocked NF-kB activation by decreasing p65 nuclear translocation, although blunting the degradation of IkBa was due, at least in part, to a decrease in IKKb kinase activity. A direct correlation was observed between increasing azithromycin concentrations and increased IKKb protein expression. Moreover, incubation with the IKKb inhibitor IKK16 decreased arginase expression and activity in azithromycin-treated cells but not in cells treated with IL-4 and IL-13. Importantly, azithromycin treatment also decreased STAT1 phosphorylation in a concentration-dependent manner, an effect that was reversed with IKK16 treatment. We conclude that azithromycin anti-inflammatory mechanisms involve inhibition of the STAT1 and NF-kB signaling pathways through the drug's effect on p65 nuclear translocation and IKKb.

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.

bThis open-label noncontrolled, phase II multicenter trial was designed to evaluate the safety, tolerability, and efficacy of 200 mg of AFN-1252, a selective inhibitor of Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI), given by mouth twice daily in the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to staphylococci. Important aspects of the current study included a comparison of early response efficacy endpoints with end-of-treatment and follow-up endpoints. Many patients in the intent-to-treat population (n ‫؍‬ 103) had significant comorbidities. The overall early response rate at day 3 was 97.3% (wound, 100%; abscess, 96.6%; cellulitis, 94.4%) in the microbiologically evaluable (ME) population. Within the ME population, 82.9% of patients had a >20% decrease in the area of erythema, and 77.9% of patients had a >20% decrease in the area of induration, on day 3. S. aureus was detected in 97.7% of patients (n ‫؍‬ 37 patients with methicillin-resistant S. aureus W idespread overuse of broad-spectrum antibiotics over the past 20 years has been associated with significant rates of antibiotic resistance, with multidrug resistance prevalent among a broad range of bacterial pathogens (1), including Staphylococcus aureus. Many experts have advocated the development of speciestargeted agents which reduce off-target selection pressures on the human microbiome and could potentially decrease such conditions as antibiotic-induced colitis and candidiasis (2). Antiinfectives that specifically target Staphylococcus spp. may be less likely to lead to the development of resistant enterococcal, pneumococcal or other common bacterial pathogens.FabI catalyzes the last step in the essential bacterial fatty acid biosynthetic pathway and is the sole form of enoyl-acyl carrier protein (ACP) reductase present in S. aureus, Staphylococcus epidermidis, and other staphylococci (3, 4, 5, 6). Other enoyl-ACP reductase enzymes are present in many bacterial species, but these are sufficiently different to enable species-specific selectivity (7). AFN-1252, a FabI inhibitor, is the result of a program tasked with finding a new antimicrobial agent specifically active against Staphylococcus spp., including methicillin-resistant S. aureus (MRSA) (8).The objective of the current proof-of-concept study was to investigate the efficacy and safety of orally administered AFN-1252 in patients with acute bacterial skin and skin structure infection (ABSSSI) due to staphylococci. The study design followed recent FDA guidance (9) on the development of drugs for the treatment of ABSSSI. The inclusion criteria were designed to identify patients with a high likelihood of having a proven staphylococcal infection to ensure a high number of microbiologically evaluable patients. MATERIALS AND METHODSAntibacterial agent. AFN-1252 (free base, AFN-12520000) was formulated as immediate-release (IR) tablets.Study design. This noncontrolled, open-label, phase II trial was designed as a proof-of-concept study to evaluate the s...

Bronchopulmonary dysplasia (BPD) refers to a heterogeneous group of lung disorders in infants that is commonly associated with prematurity and surfactant deficiency. BPD results from the complex interplay between impairments in the premature lung such as surfactant deficiency, perinatal insults such as infection, and damage resulting from supportive care of the infant due to barotrauma or volutrauma from mechanical ventilation and oxygen toxicity from supplemental oxygen administration. These factors result in chronic inflammation in the infant lung with recurring cycles of lung damage and repair that may impair alveolarization and vascularization in the developing lungs. As our insight in how to treat BPD improves along with the ability to do so with developing technology and therapies, the underlying pathogenesis will also change. The term ‘new’ BPD is now commonly used, to describe the changes seen in the post-surfactant era. This discussion reviews the pathogenesis of BPD according to the current medical literature.

Interspecies differences in drug metabolism have made it difficult to use preclinical animal testing data to predict the drug metabolites or potential drug-drug interactions (DDIs) that will occur in humans. Although chimeric mice with humanized livers can produce known human metabolites for test substrates, we do not know whether chimeric mice can be used to prospectively predict human drug metabolism or a possible DDI. Therefore, we investigated whether they could provide a more predictive assessment for clemizole, a drug in clinical development for the treatment of hepatitis C virus (HCV) infection. Our results demonstrate, for the first time, that analyses performed in chimeric mice can correctly identify the predominant human drug metabolite before human testing. The differences in the rodent and human pathways for clemizole metabolism were of importance, because the predominant human metabolite was found to have synergistic anti-HCV activity. Moreover, studies in chimeric mice also correctly predicted that a DDI would occur in humans when clemizole was coadministered with a CYP3A4 inhibitor. These results demonstrate that using chimeric mice can improve the quality of preclinical drug assessment.

The use of daptomycin has been associated with an elevation in creatine phosphokinase level, with a reported incidence of 2.8% in phase III clinical trials. Published case reports have documented the presence of myopathy in patients who received daptomycin; however, there have been no previously reported cases of rhabdomyolysis in animals or humans to date. We describe a case of rhabdomyolysis during therapy with daptomycin.