The use of macrolide antibiotics in patients with cystic fibrosis.
ABSTRACT 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.
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ABSTRACT: Conventional antibiotics target the growth and the basal life processes of bacteria leading to growth arrest and cell death. The selective force that is inherently linked to this mode of action eventually selects out antibiotic-resistant variants. The most obvious alternative to antibiotic-mediated killing or growth inhibition would be to attenuate the bacteria with respect to pathogenicity. The realization that Pseudomonas aeruginosa, and a number of other pathogens, controls much of their virulence arsenal by means of extracellular signal molecules in a process denoted quorum sensing (QS) gave rise to a new 'drug target rush'. Recently, QS has been shown to be involved in the development of tolerance to various antimicrobial treatments and immune modulation. The regulation of virulence via QS confers a strategic advantage over host defences. Consequently, a drug capable of blocking QS is likely to increase the susceptibility of the infecting organism to host defences and its clearance from the host. The use of QS signal blockers to attenuate bacterial pathogenicity, rather than bacterial growth, is therefore highly attractive, particularly with respect to the emergence of multi-antibiotic resistant bacteria.Philosophical Transactions of The Royal Society B Biological Sciences 08/2007; 362(1483):1213-22. DOI:10.1098/rstb.2007.2046 · 6.31 Impact Factor
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ABSTRACT: Pseudomonas aeruginosa is an opportunistic human pathogen that causes chronic biofilm-based infections in host organisms. P. aeruginosa employs quorum sensing (QS) to control expression of its virulence, and to establish and maintain chronic infections. Under such conditions, the biofilm mode of growth contributes significantly to P. aeruginosa tolerance to the action of the innate and adaptive defence system and numerous antibiotics. In the present study, an in vivo foreign-body infection model was established in the peritoneal cavity of mice. Experimental data showed that QS-deficient P. aeruginosa are cleared more rapidly from silicone implants as compared to their wild-type counterparts. Concurrently, treatment with the QS inhibitor furanone C-30 of mice harbouring implants colonized with the wild-type P. aeruginosa resulted in a significantly faster clearing of the implants as compared to the placebo-treated group. These results were obtained with both an inbred (BALB/c) and an outbred (NMRI) mouse strain. The present results support a model by which functional QS systems play a pivotal role in the ability of bacteria to resist clearing by the innate immune system and strongly suggest that the efficiency of the mouse innate defence against biofilm-forming P. aeruginosa is improved when the bacteria are treated with QS drugs that induce QS deficiency.Microbiology 08/2007; 153(Pt 7):2312-20. DOI:10.1099/mic.0.2007/006122-0 · 2.84 Impact Factor
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ABSTRACT: Interference of antibacterial agents with the immune system, and its possible clinical implications, has long been a focus of attention worldwide. Toxic effects with immunological implications (neutropenia, allergy, etc.) exerted an influence on the therapeutic choice early in the antimicrobial era, but attention has gradually shifted to beneficial “immunomodulatory” properties. Many papers in this field have been published and it has been periodically reviewed [1, 2]. Interest in “immunostimulation” peaked in the 1970s. Only recently have the potential benefits of downregulating immunomodulators entered the limelight, with the understanding that immune hyperactivation (in sepsis and inflammatory/autoimmune diseases, for example) can also have disastrous consequences. Incidental observations that some non-infectious diseases, including inflammatory disorders, may be improved by antibacterials have bolstered interest in the immunomodulatory activity of this class of drugs. An improved knowledge of the immune system and its regulation, as well as technological advances, has facilitated such investigations. With a growing number of supportive experimental and clinical studies, the relevance of the immunomodulatory actions of some antibiotics for their therapeutic efficacy in various diseases is now generally admitted.