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Macrolides for the therapy of nosocomial infections.

Nosocomial infections are an emerging threat. Available solutions are limited due to the multidrug-resistance pattern of the pathogens. Macrolides modulate the immune function of the host and may be active in this setting.

RECENT FINDINGS: Findings of in-vitro and experimental animal studies are presented. Clinical studies of community-acquired pneumonia (CAP) and ventilator-associated pneumonia (VAP) are described.

SUMMARY: Macrolides decrease production of proinflammatory cytokines by circulating monocytes and by alveolar macrophages and decrease apoptosis of circulating lymphocytes in animal models of acute infections. They also inhibit gene expression of proteins participating in quorum sensing of Pseudomonas aeruginosa. Retrospective cohort studies indicate that addition of a macrolide significantly improves outcome in severe CAP. One randomized, double-blind, clinical study is available. This involves patients with VAP allocated to placebo or intravenous clarithromycin 1 g once daily for 3 days. Clarithromycin treatment significantly decreased time to resolution of VAP and time until weaning from mechanical ventilation. The described findings are promising for the use of macrolides in nosocomial infections.

Is healthcare-associated pneumonia a distinct entity needing specific therapy?

Healthcare-associated pneumonia (HCAP) was introduced in 2005 by American Thoracic Society/Infectious Diseases Society of America guidelines as a new entity of pneumonia, resembling nosocomial pneumonia rather than community-acquired pneumonia (CAP) in terms of frequency of multidrug-resistant (MDR) pathogens and outcomes, thus requiring broad spectrum initial antimicrobial coverage in order to prevent inadequate treatment and, as a consequence, excess mortality. This concept continues to be a subject of controversy. Main concerns relate to the definition of HCAP, the true frequency of MDR pathogens, and the impact of MDR pathogens on outcomes.

RECENT FINDINGS: Definitions of HCAP and the relative frequencies of HCAP defining subgroups were highly variable. All studies demonstrated an increased severity of pneumonia at presentation and an excess mortality from HCAP as compared to CAP. The incidence of MDR pathogens in different observational studies was slightly increased but generally low in most studies originating from Europe, South Korea, Canada, and Japan. However, the data do not support a causal relationship of MDR incidence and excess mortality. Instead, after adjustment for confounders, mortality might be related to hidden or documented treatment restrictions in elderly and severely disabled patients. Accordingly, HCAP guideline concordant antimicrobial treatment did not improve outcomes.

SUMMARY: The HCAP concept is based on varying definitions poorly predictive of MDR pathogens. The incidence of MDR pathogens is far lower than supposed in the original guideline document, and MDR pathogens do not seem to be the main cause of excess mortality. Broad antimicrobial coverage does not alter outcomes. As the HCAP concept results in a tremendous overtreatment without any evidence for improved outcomes, it should not be implemented in clinical practice prior to clear evidence that it is superior to a careful assessment of individual risk factors for MDR pathogens.

New therapy options for MRSA with respiratory infection/pneumonia.

Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent causative agent of nosocomial pneumonia. Because of important clinical consequences of inappropriate treatment, a current review of the potential modifications undergone by S. aureus and adaptation to new treatment options is necessary.

RECENT FINDINGS: Vancomycin has been considered the treatment of choice for pneumonia due to MRSA. However, detection of a progressive increase in the minimum inhibitory concentration for this antibiotic, its limited access to the lung parenchyma, and its considerable adverse effects have called into question its position. Linezolid has been shown to have a better pharmacokinetic and safety profiles. The prior uncertainty regarding the clinical superiority of linezolid appears to have been resolved with the publication of a recent trial. Linezolid achieved a higher clinical and microbiological response rate (the latter was not statistically significant), together with a lower incidence of all types of renal adverse effects in patients with nosocomial pneumonia, compared with vancomycin. Tigecycline, teicoplanin and quinupristin/dalfopristin were inferior to the compared drug in their respective clinical trials. The clinical efficacy of telavancin was similar to that of vancomycin. The renal adverse effects of telavancin have to be clarified. Other drugs are efficacious against MRSA but their profile should be evaluated in nosocomial pneumonia.

SUMMARY: Current therapeutic alternatives for nosocomial pneumonia due to MRSA appear to be limited to vancomycin and linezolid. However, vancomycin pitfalls, together with the apparent clinical superiority of linezolid, appear to restrict its indication. Telavancin could be a good alternative in patients without basal renal failure.

MicroRNAs in lung diseases

The advent of RNA sequencing technology has stimulated rapid advances in our understanding of the transcriptome, including discovery of the vast RNA complement generated by transcript splice variation and the expansion of our knowledge of non-coding RNAs. One non-coding RNA subtype, microRNAs (miRNAs), are particularly well studied, primarily because of their important roles as post-transcriptional gene regulators. The first miRNA was identified in the early 1990s and there are now thought to be around 1000 distinct miRNAs in man, with each cell type expressing a distinct repertoire. Increasing evidence has implicated miRNAs as having causative roles in a variety of lung diseases and has driven investigations into their potential as therapeutic targets.

Gene expression networks in COPD: microRNA and mRNA regulation

Background

The mechanisms underlying chronic obstructive pulmonary disease (COPD) remain unclear. MicroRNAs (miRNAs or miRs) are small non-coding RNA molecules that modulate the levels of specific genes and proteins. Identifying expression patterns of miRNAs in COPD may enhance our understanding of the mechanisms of disease. A study was undertaken to determine if miRNAs are differentially expressed in the lungs of smokers with and without COPD. miRNA and mRNA expression were compared to enrich for biological networks relevant to the pathogenesis of COPD.

 Methods

Lung tissue from smokers with no evidence of obstructive lung disease (n=9) and smokers with COPD (n=26) was examined for miRNA and mRNA expression followed by validation. We then examined both miRNA and mRNA expression to enrich for relevant biological pathways.

 Results

70 miRNAs and 2667 mRNAs were differentially expressed between lung tissue from subjects with COPD and smokers without COPD. miRNA and mRNA expression profiles enriched for biological pathways that may be relevant to the pathogenesis of COPD including the transforming growth factor β, Wnt and focal adhesion pathways. miR-223 and miR-1274a were the most affected miRNAs in subjects with COPD compared with smokers without obstruction. miR-15b was increased in COPD samples compared with smokers without obstruction and localised to both areas of emphysema and fibrosis. miR-15b was differentially expressed within GOLD classes of COPD. Expression of SMAD7, which was validated as a target for miR-15b, was decreased in bronchial epithelial cells in COPD.

 Conclusions

miRNA and mRNA are differentially expressed in individuals with COPD compared with smokers without obstruction. Investigating these relationships may further our understanding of the mechanisms of disease.

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