Molecular Epidemiology of Chronic Pseudomonas aeruginosa Airway Infections in Cystic Fibrosis

Cramer, Nina; Wiehlmann, Lutz; Ciofu, Oana; Tamm, Stephanie; Høiby, Niels; Tümmler, Burkhard

doi:10.1371/journal.pone.0050731

Cited by 63 publications

(77 citation statements)

References 36 publications

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“…The MICs of POL7001 and comparators were determined against a panel of P. aeruginosa CF strains (Table 1). P. aeruginosa lineages from nine CF patients, longitudinally collected during a period of up to 16 years and comprising 17 "early," 6 "intermediate," and 17 "late" isolates, were included in the study (19). Clonal P. aeruginosa isolates of each lineage showed different phenotypes that changed during genetic adaptation in CF lung (10,20,21).…”

Section: Resultsmentioning

confidence: 99%

Efficacy of the Novel Antibiotic POL7001 in Preclinical Models of Pseudomonas aeruginosa Pneumonia

Cigana

Bernardini

Facchini

et al. 2016

Antimicrob Agents Chemother

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The clinical development of antibiotics with a new mode of action combined with efficient pulmonary drug delivery is a priority against untreatable Pseudomonas aeruginosa lung infections. POL7001 is a macrocycle antibiotic belonging to the novel class of protein epitope mimetic (PEM) molecules with selective and potent activity against P. aeruginosa. We investigated ventilatorassociated pneumonia (VAP) and cystic fibrosis (CF) as indications of the clinical potential of POL7001 to treat P. aeruginosa pulmonary infections. MICs of POL7001 and comparators were measured for reference and clinical P. aeruginosa strains. The therapeutic efficacy of POL7001 given by pulmonary administration was evaluated in murine models of P. aeruginosa acute and chronic pneumonia. POL7001 showed potent in vitro activity against a large panel of P. aeruginosa isolates from CF patients, including multidrug-resistant (MDR) isolates with adaptive phenotypes such as mucoid or hypermutable phenotypes. The efficacy of POL7001 was demonstrated in both wild-type and CF mice. In addition to a reduced bacterial burden in the lung, POL7001-treated mice showed progressive body weight recovery and reduced levels of inflammatory markers, indicating an improvement in general condition. Pharmacokinetic studies indicated that POL7001 reached significant concentrations in the lung after pulmonary administration, with low systemic exposure. These results support the further evaluation of POL7001 as a novel therapeutic agent for the treatment of P. aeruginosa pulmonary infections. Pseudomonas aeruginosa is a difficult-to-treat human pathogen causing a wide range of infections, especially in the respiratory tract. These infections, such as ventilator-associated pneumonia (VAP), are often life-threatening. Cystic fibrosis (CF) is another disease where P. aeruginosa lung infections are associated with worse outcomes (1). The high prevalence of P. aeruginosa infections, in nearly 80% of CF patients Ͼ18 years of age (2), is partially due to the propensity of this species to form biofilms and cause chronic infection.Frequently observed inefficacy of available treatments is due to intrinsic or acquired resistance of P. aeruginosa and/or limited penetration of antibiotics into biofilms (3). However, despite the need for new drugs, only few novel antipseudomonal drugs or modifications of existing molecules are currently in the late stage of preclinical or clinical development (4). A new family of potent protein epitope mimetic (PEM) antibiotics has recently been described. These molecules show selective activity against P. aeruginosa by inhibiting the transport of the lipopolysaccharide to the outer membrane (5). Among these antibiotics, we showed that POL7001 provided protection against lethal P. aeruginosa infection in a mouse septicemia model (5).In this work, to investigate the efficacy of POL7001 in models relevant for VAP or CF, we used murine P. aeruginosa acute and chronic pneumonia, including in CF mice. We report that pulmonary delivery of POL7001 is e...

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Section: Resultsmentioning

confidence: 99%

Efficacy of the Novel Antibiotic POL7001 in Preclinical Models of Pseudomonas aeruginosa Pneumonia

Cigana

Bernardini

Facchini

et al. 2016

Antimicrob Agents Chemother

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“…These results are consistent with the literature (36), and they highlight the fact that chronic infections are due to P. aeruginosa strains derived from various environmental reservoirs (37). Cramer et al (38) revealed in their study that there are 20 ubiquitous clones frequently found and that, for the CF population, the five most commonly isolated clones belong to these 20 clones.…”

Section: Discussionmentioning

confidence: 97%

Pseudomonas aeruginosa and Periodontal Pathogens in the Oral Cavity and Lungs of Cystic Fibrosis Patients: a Case-Control Study

Caldas

Gall

Revert³

et al. 2015

J Clin Microbiol

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bCystic fibrosis (CF) is the most frequent lethal genetic disease in the Caucasian population. Lung destruction is the principal cause of death by chronic Pseudomonas aeruginosa colonization. There is a high prevalence of oropharyngeal anaerobic bacteria in sputum of CF patients. This study was carried out due to the lack of results comparing subgingival periodontal pathogenic bacteria between the oral cavity and lungs in patients with CF in relation with P. aeruginosa presence. Our first goal was to detect P. aeruginosa in oral and sputum samples by culture and molecular methods and to determine clonality of isolates. In addition, subgingival periodontal anaerobic bacteria were searched for in sputum. A cross-sectional pilot case-control study was conducted in the CF Reference Center in Roscoff, France. Ten CF patients with a ⌬F508 homozygous mutation (5 chronically colonized [CC] and 5 not colonized [NC]) were enrolled. P. aeruginosa was detected in saliva, sputum, and subgingival plaque samples by real-time quantitative PCR (qPCR). Subsequently, periodontal bacteria were also detected and quantified in subgingival plaque and sputum samples by qPCR. In CC patients, P. aeruginosa was recovered in saliva and subgingival plaque samples. Sixteen P. aeruginosa strains were isolated in saliva and sputum from this group and compared by pulsed-field gel electrophoresis (PFGE). Subgingival periodontal anaerobic bacteria were found in sputum samples. A lower diversity of these species was recovered in the CC patients than in the NC patients. The presence of the same P. aeruginosa clonal types in saliva and sputum samples underlines that the oral cavity is a possible reservoir for lung infection.

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“…In the German collection, higher resistance is essentially related to the presence of more sporadic MDR clones than in the two other countries. We cannot exclude differences in therapeutic management of patients among these three centers that may influence resistance selection (48), but this specific aspect was not within the scope of our study.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial Susceptibility of Pseudomonas aeruginosa Isolated from Cystic Fibrosis Patients in Northern Europe

Mustafa

Chalhoub

Denis

et al. 2016

Antimicrob Agents Chemother

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f Pseudomonas aeruginosa is a major cause of morbidity and mortality in cystic fibrosis patients. This study compared the antimicrobial susceptibilities of 153 P. aeruginosa isolates from the United Kingdom (UK) (n ‫؍‬ 58), Belgium (n ‫؍‬ 44), and Germany (n ‫؍‬ 51) collected from 118 patients during routine visits over the period from 2006 to 2012. MICs were measured by broth microdilution. Genes encoding extended-spectrum ␤-lactamases (ESBL), metallo-␤-lactamases, and carbapenemases were detected by PCR. Pulsed-field gel electrophoresis and multilocus sequence typing were performed on isolates resistant to >3 antibiotic classes among the penicillins/cephalosporins, carbapenems, fluoroquinolones, aminoglycosides, and polymyxins. Based on EUCAST/CLSI breakpoints, susceptibility rates were <30%/<40% (penicillins, ceftazidime, amikacin, and ciprofloxacin), 44 to 48%/48 to 63% (carbapenems), 72%/72% (tobramycin), and 92%/78% (colistin) independent of patient age. Sixty percent of strains were multidrug resistant (MDR; European Centre for Disease Prevention and Control criteria). Genes encoding the most prevalent ESBL (BEL, PER, GES, VEB, CTX-M, TEM, SHV, and OXA), metallo-␤-lactamases (VIM, IMP, and NDM), or carbapenemases (OXA-48 and KPC) were not detected. The Liverpool epidemic strain (LES) was prevalent in UK isolates only (75% of MDR isolates). Four MDR sequence type 958 (ST958) isolates were found to be spread over the three countries. The other MDR clones were evidenced in <3 isolates and localized in a single country. A new sequence type (ST2254) was discovered in one MDR isolate in Germany. Clonal and nonclonal isolates with different susceptibility profiles were found in 20 patients. Thus, resistance and MDR are highly prevalent in routine isolates from 3 countries, with meropenem, tobramycin, and colistin remaining the most active drugs.

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Molecular Epidemiology of Chronic Pseudomonas aeruginosa Airway Infections in Cystic Fibrosis

Cited by 63 publications

References 36 publications

Efficacy of the Novel Antibiotic POL7001 in Preclinical Models of Pseudomonas aeruginosa Pneumonia

Efficacy of the Novel Antibiotic POL7001 in Preclinical Models of Pseudomonas aeruginosa Pneumonia

Pseudomonas aeruginosa and Periodontal Pathogens in the Oral Cavity and Lungs of Cystic Fibrosis Patients: a Case-Control Study

Antimicrobial Susceptibility of Pseudomonas aeruginosa Isolated from Cystic Fibrosis Patients in Northern Europe

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