Development of antibiotic resistance in <i>Pseudomonas aeruginosa</i> during two decades of antipseudomonal treatment at the Danish CF Center

Ciofu, Oana; Giwercman, Birgit; Høiby, Niels; Pedersen, Susanne Juhl

doi:10.1111/j.1699-0463.1994.tb05219.x

Cited by 83 publications

(60 citation statements)

References 22 publications

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“…These results are in agreement with previous studies (Ciofu et al, 1994), showing development of resistance to antibiotics in P. aeruginosa isolates during chronic lung infection.…”

supporting

confidence: 94%

Genetic adaptation of Pseudomonas aeruginosa during chronic lung infection of patients with cystic fibrosis: strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants

et al. 2010

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During the chronic lung infection of patients with cystic fibrosis (CF), Pseudomonas aeruginosa can survive for long periods due to adaptive evolution mediated by genetic variation. Hypermutability is considered to play an important role in this adaptive evolution and it has been demonstrated that mutator populations are amplified in the CF lung by hitchhiking with adaptive mutations. Two of the genes that are frequently mutated in isolates from chronic infection are mucA and lasR. Loss-of-function mutations in these genes determine the phenotypic switch to mucoidy and loss of quorum sensing, which are considered hallmarks of chronic virulence. The aims of our study were to investigate (1) the genetic background of the P. aeruginosa subpopulations with non-mutator, weak or strong mutator phenotype and their dynamics during the chronic lung infection, and (2) the time sequence in which the hypermutable, mucoid and quorum-sensing-negative phenotypes emerge during chronic lung infection. For these purposes the sequences of mutS, mutL, uvrD, mutT, mutY and mutM anti-mutator genes as well as of mucA and lasR were analysed in 70 sequential P. aeruginosa isolates obtained from the respiratory secretions of 10 CF patients (one to three isolates per time point). Analysis of the genetic background of the mutator phenotype showed that mutS was the most commonly affected gene followed by mutL in isolates with strong mutator phenotype. The mutT, mutY, mutM genes were affected in isolates with low fold-changes in the mutation frequencies compared to the reference strain PAO1. Isolates with non-mutator, weak or strong mutator phenotype were represented at all time points showing co-existence of these subpopulations, which suggests parallel evolution of the various mutators in the different focal niches of infection in the CF lung. Mutations in mucA and lasR occurred earlier than mutations in the anti-mutator genes, showing that hypermutability is not a prerequisite for the acquisition of mucoidy and loss of quorum sensing, considered hallmarks of chronic virulence. Significantly higher mutation rates and MICs of ceftazidime, meropenem and ciprofloxacin were found for isolates collected late (more than 10 years) during the chronic lung infection compared to isolates collected earlier, which suggests an amplification of the mutator subpopulation by hitchhiking with development of antibiotic resistance. Similar evolutionary pathways concordant with adaptive radiation were observed in different clonal lineages of P. aeruginosa from CF patients.

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“…These results are in agreement with previous studies (Ciofu et al, 1994), showing development of resistance to antibiotics in P. aeruginosa isolates during chronic lung infection.…”

supporting

confidence: 94%

Genetic adaptation of Pseudomonas aeruginosa during chronic lung infection of patients with cystic fibrosis: strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants

et al. 2010

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“…Studies carried out at the Danish CF Center in Copenhagen (Ciofu et al, 1994) have shown the development of bacterial resistance to antibiotics to be a serious side-effect of the current anti-pseudomonal treatment, and it highlights the importance of the development of therapies that limit the formation of persistent biofilms in the lungs. A balance between colonization and clearance causes the slow development of chronic P. aeruginosa infection.…”

Section: Resultsmentioning

confidence: 99%

Garlic blocks quorum sensing and promotes rapid clearing of pulmonary Pseudomonas aeruginosa infections

et al. 2005

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The opportunistic human pathogen Pseudomonas aeruginosa is the predominant micro-organism of chronic lung infections in cystic fibrosis patients. P. aeruginosa colonizes the lungs by forming biofilm microcolonies throughout the lung. Quorum sensing (QS) renders the biofilm bacteria highly tolerant to otherwise lethal doses of antibiotics, and protects against the bactericidal activity of polymorphonuclear leukocytes (PMNs). It has been previously demonstrated that QS is inhibited by garlic extract. In this study, the synergistic effects of garlic and tobramycin, and PMNs activities have been evaluated. P. aeruginosa was grown in vitro in continuous-culture once-through flow chambers with and without garlic extract. The garlic-treated biofilms were susceptible to both tobramycin and PMN grazing. Furthermore, the PMNs showed an increase in respiratory burst activation, when incubated with the garlic-treated biofilm. Garlic extract was administered as treatment for a mouse pulmonary infection model. Mice were treated with garlic extract or placebo for 7 days, with the initial 2 days being prophylactic before P. aeruginosa was instilled in the left lung of the mice. Bacteriology, mortality, histopathology and cytokine production were used as indicators. The garlic treatment initially provoked a higher degree of inflammation, and significantly improved clearing of the infecting bacteria. The results indicate that a QS-inhibitory extract of garlic renders P. aeruginosa sensitive to tobramycin, respiratory burst and phagocytosis by PMNs, as well as leading to an improved outcome of pulmonary infections.

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“…Chronic suppressive therapy (maintenance therapy) successfully maintains, or at least slows the decline of pulmonary function and prolongs the life of patients for many years [51]. The side-effects of the maintenance therapy can include high levels of conventional resistance in the persisting strains and high levels of allergies to the beta-lactam antibiotics [52][53]. Similar principles as used in CF patients are gradually being introduced in other areas of biofilm infection treatment [10][11]54]: a) systemic or local prophylactic use of antibiotics to prevent biofilm formation, b) early aggressive eradication therapy to eradicate planktonic growth or early biofilm formation and c) chronic suppressive antibiotic therapy to maintain the function of inserted foreign bodies etc.…”

Section: Figurementioning

confidence: 99%

The clinical impact of bacterial biofilms

Høiby¹,

Ciofu²,

Johansen³

et al. 2011

Int J Oral Sci

735

536

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Bacteria survive in nature by forming biofilms on surfaces and probably most, if not all, bacteria (and fungi) are capable of forming biofilms. A biofilm is a structured consortium of bacteria embedded in a self-produced polymer matrix consisting of polysaccharide, protein and extracellular DNA. Bacterial biofilms are resistant to antibiotics, disinfectant chemicals and to phagocytosis and other components of the innate and adaptive inflammatory defense system of the body. It is known, for example, that persistence of staphylococcal infections related to foreign bodies is due to biofilm formation. Likewise, chronic Pseudomonas aeruginosa lung infections in cystic fibrosis patients are caused by biofilm growing mucoid strains. Gradients of nutrients and oxygen exist from the top to the bottom of biofilms and the bacterial cells located in nutrient poor areas have decreased metabolic activity and increased doubling times. These more or less dormant cells are therefore responsible for some of the tolerance to antibiotics. Biofilm growth is associated with an increased level of mutations. Bacteria in biofilms communicate by means of molecules, which activates certain genes responsible for production of virulence factors and, to some extent, biofilm structure. This phenomenon is called quorum sensing and depends upon the concentration of the quorum sensing molecules in a certain niche, which depends on the number of the bacteria. Biofilms can be prevented by antibiotic prophylaxis or early aggressive antibiotic therapy and they can be treated by chronic suppressive antibiotic therapy. Promising strategies may include the use of compounds which can dissolve the biofilm matrix and quorum sensing inhibitors, which increases biofilm susceptibility to antibiotics and phagocytosis.

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Development of antibiotic resistance in Pseudomonas aeruginosa during two decades of antipseudomonal treatment at the Danish CF Center

Cited by 83 publications

References 22 publications

Genetic adaptation of Pseudomonas aeruginosa during chronic lung infection of patients with cystic fibrosis: strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants

Genetic adaptation of Pseudomonas aeruginosa during chronic lung infection of patients with cystic fibrosis: strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants

Garlic blocks quorum sensing and promotes rapid clearing of pulmonary Pseudomonas aeruginosa infections

The clinical impact of bacterial biofilms

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