Mini review
Prevention of Pseudomonas aeruginosa infection in cystic fibrosis patients

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Abstract

In patients with cystic fibrosis (CF) prevention of lung infections with Pseudomonas aeruginosa is of major importance. Principles to achieve this goal include vaccination, immediate use of antibiotics in patients newly colonized with the pathogen, and hygienic measures. The purpose of this review is to discuss recent developments in this context.

Introduction

The prognosis of patients with the hereditary disease cystic fibrosis (CF) is substantially dependent on chronic respiratory infection and inflammation, a hallmark of CF. The Gram-negative bacterial opportunistic pathogen Pseudomonas aeruginosa which causes severe nosocomial and community-acquired infections at various body sites, is still the dominant pathogen today in patients with CF, where it causes lower respiratory tract infections (Cystic Fibrosis Foundation Patient Registry, 2008, Driscoll et al., 2007, Döring and Ratjen, 2007).

In CF patients, multiple mutations occur in the causative gene, coding for an epithelial chloride channel, named CF transmembrane conductance regulator (CFTR) (Cystic Fibrosis Genetic Analysis Consortium, 2007). Mutations in CFTR lead to a number of defective mechanisms in innate immunity which facilitate airway colonization with bacterial pathogens including P. aeruginosa and Staphylococcus aureus (Döring and Gulbins, 2009). To prevent lung infections with P. aeruginosa, several strategies have been pursued including the development of vaccines, the use of antibiotics in patients newly colonized with the pathogen, and hygienic measures.

Unfortunately, at present there is no P. aeruginosa vaccine available on the market, although many other patient groups at risk for severe P. aeruginosa infections, including paraplegic and burn patients, patients hospitalized in intensive care units especially when undergoing mechanical ventilation, may develop P. aeruginosa infections. The vast majority of vaccine studies are preclinical, and only 2 vaccines have been tested in phase III studies in CF patients (Döring and Pier, 2008, Lang et al., 2004). A threatening aspect in this context is that, like other bacterial pathogens, P. aeruginosa may become resistant to multiple antibiotics (Cheng et al., 1996, Lechtzin et al., 2006, Salunkhe et al., 2005), particularly in CF patients which receive many courses of antibiotics in their life time. Several reasons may explain the lack of progress in P. aeruginosa vaccine development for CF patients: (1) the difficulties in testing the efficacy of potential vaccines in randomized, double-blinded, placebo-controlled phase III trials in a patient group which is heavily treated with antibiotics; (2) the inherent defective mechanisms of innate immunity in CF airways; and (3) the relatively low number of CF patients.

In contrast to the P. aeruginosa vaccine development, the use of antibiotics in CF patients newly colonized with the pathogen, has been a success story, due to the high efficacy of various antibiotics to eradicate P. aeruginosa for longer periods of time from the respiratory tract of the patients (Döring and Høiby, 2004). This strategy has shifted the prevalence of chronic P. aeruginosa lung infection in the CF center in Copenhagen, Denmark, to CF patients with ages higher than 15 years. Also the separation of infected patients from uninfected, susceptible patients and the implementation of hygienic measures have been successful to prevent particularly cross-infection with P. aeruginosa (Döring and Høiby, 2004).

The purpose of this review is to discuss recent developments concerning vaccination, use of antibiotics in patients newly colonized with P. aeruginosa, and the application of hygienic measures to prevent P. aeruginosa lung infections in CF patients. The interested reader is also referred to other reviews on this topic (Döring and Høiby, 2004, Saiman and Siegel, 2004, Ramsey and Wozniak, 2005, Pier, 2003, Sedlak-Weinstein et al., 2005, Holder, 2004, Döring and Pier, 2008, Farrell et al., 2008, Geller, 2009).

Section snippets

P. aeruginosa vaccines

Based on the findings that P. aeruginosa changes its phenotype in infected airways of CF patients from single bacterial cells towards mucoid biofilms which are characterized by the production of the exopolysaccharide alginate, alginate vaccines have been proposed. Alginate (sometimes referred to as mucoid exopolysaccharide, MEP) is a random ß1-4-linked polymer of d-mannuronic acid (M) and l-guluronic acid (G) residues (Skjak-Braek et al., 1986), revealing variable levels of O-acetylation at the

Prevention of P. aeruginosa infection by antibiotics

The observation that the P. aeruginosa strains, initially colonizing the CF airways, are single non-mucoid cells which only after some time change their phenotype into mucoid biofilms which are very difficult to treat with antibiotics, has prompted studies to treat P. aeruginosa colonization very early. This antibiotic treatment strategy has successfully eradicated P. aeruginosa from CF airways for considerable time periods and prolonged the onset of chronic infection in many European CF

Application of hygienic principles to prevent lung disease in CF patients

P. aeruginosa is ubiquitous in moist environments (Botzenhart and Döring, 1993) and particularly aerosols generated from toilets, sink drains, whirl pools, and dental equipment, containing high numbers of bacterial cells have been thought to be important for the transmission of pathogens to the airways of CF patients (Döring et al., 1991, Döring et al., 1996, Jensen et al., 1997, Hollyoak et al., 1995). In addition, transmission via P. aeruginosa-contaminated hands of P. aeruginosa-infected CF

Conclusions

In CF, a remarkable number of innate immune functions are dysregulated as consequences of mutations in CFTR. Synergistically, they may provoke lung disease in virtually all subjects caused by various microbial organisms adapted to this specific environmental niche including P. aeruginosa. Active vaccination against P. aeruginosa is thought to prevent lung disease with this pathogen to some extent, however, although many potential vaccine antigen candidates have been tested in preclinical

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