Antimicrobial resistance in the respiratory microbiota of people with cystic fibrosis

Sherrard, L.; Tunney, Michael; Elborn, J. Stuart

doi:10.1016/s0140-6736(14)61137-5

Cited by 124 publications

(119 citation statements)

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“…The improved survival of CF patients, due in part to the chronic administration of antibiotics, has compounded the problems associated with resistance to antibiotic treatment (35,36). With the rapid emergence of antibiotic resistance, the development of new therapies is essential.…”

Section: Discussionmentioning

confidence: 99%

A Low-Molecular-Weight Alginate Oligosaccharide Disrupts Pseudomonal Microcolony Formation and Enhances Antibiotic Effectiveness

Pritchard

Powell

Jack

et al. 2017

Antimicrob Agents Chemother

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In chronic respiratory disease, the formation of dense, 3-dimensional "microcolonies" by Pseudomonas aeruginosa within the airway plays an important role in contributing to resistance to treatment. An in vitro biofilm model of pseudomonal microcolony formation using artificial-sputum (AS) medium was established to study the effects of low-molecular-weight alginate oligomers (OligoG CF-5/20) on pseudomonal growth, microcolony formation, and the efficacy of colistin. The studies employed clinical cystic fibrosis (CF) isolates (n ϭ 3) and reference nonmucoid and mucoid multidrug-resistant (MDR) CF isolates (n ϭ 7). Bacterial growth and biofilm development and disruption were studied using cell viability assays and image analysis with scanning electron and confocal laser scanning microscopy. Pseudomonal growth in AS medium was associated with increased ATP production (P Ͻ 0.05) and the formation (at 48 h) of discrete (Ͼ10-m) microcolonies. In conventional growth medium, colistin retained an ability to inhibit growth of planktonic bacteria, although the MIC was increased (0.1 to 0.4 g/ml) in AS medium compared to Mueller-Hinton (MH) medium. In contrast, in an established-biofilm model in AS medium, the efficacy of colistin was decreased. OligoG CF-5/20 (Ն2%) treatment, however, induced dose-dependent biofilm disruption (P Ͻ 0.05) and led to colistin retaining its antimicrobial activity (P Ͻ 0.05). While circular dichroism indicated that OligoG CF-5/20 did not change the orientation of the alginate carboxyl groups, mass spectrometry demonstrated that the oligomers induced dose-dependent (Ͼ0.2%; P Ͻ 0.05) reductions in pseudomonal quorum-sensing signaling. These findings reinforce the potential clinical significance of microcolony formation in the CF lung and highlight a novel approach to treat MDR pseudomonal infections.

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Section: Discussionmentioning

confidence: 99%

A Low-Molecular-Weight Alginate Oligosaccharide Disrupts Pseudomonal Microcolony Formation and Enhances Antibiotic Effectiveness

Pritchard

Powell

Jack

et al. 2017

Antimicrob Agents Chemother

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“…CF mice treated with POL7001 showed significantly improved weight gain and reduced bacterial load in the lung compared to animals treated with the vehicle. It has been reported that CF is a difficult environment which may reduce the efficacy of treatments (39). Repeated treatment with POL7001 showed similar beneficial effects in mice with different genetic a C57BL/6 Cftr tm1UNC TgN(FABPCFTR)#Jaw (CF) mice and the corresponding wt congenic mice (non-CF) (11 to 18 weeks of age) were infected with MDR-RP73 embedded in agar beads and treated with saline solution or POL7001 (2 mg/kg) by the use of a Penn-Century device according to the schedule shown in Fig.…”

Section: Discussionmentioning

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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“…During bacterial biofilm growth and maturation, cells continue to deposit an extracellular matrix, which plays roles in cell cohesion (106,133,134), gas exchange (104), drug resistance (21,(135)(136)(137), defense against penetration by white blood cells (138)(139)(140)(141)(142), and the maintenance of architecture and biofilm rigidity (106,143,144). The ECM is hydrated and therefore is composed primarily of water.…”

Section: Defining a C Albicans Biofilm: Lessons From Bacteriamentioning

confidence: 99%

Plasticity of Candida albicans Biofilms

Soll

Daniels

2016

Microbiol Mol Biol Rev

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SUMMARYCandida albicans, the most pervasive fungal pathogen that colonizes humans, forms biofilms that are architecturally complex. They consist of a basal yeast cell polylayer and an upper region of hyphae encapsulated in extracellular matrix. However, biofilms formedin vitrovary as a result of the different conditions employed in models, the methods used to assess biofilm formation, strain differences, and, in a most dramatic fashion, the configuration of the mating type locus (MTL). Therefore, integrating data from different studies can lead to problems of interpretation if such variability is not taken into account. Here we review the conditions and factors that cause biofilm variation, with the goal of engendering awareness that more attention must be paid to the strains employed, the methods used to assess biofilm development, every aspect of the model employed, and the configuration of theMTLlocus. We end by posing a set of questions that may be asked in comparing the results of different studies and developing protocols for new ones. This review should engender the notion that not all biofilms are created equal.

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Antimicrobial resistance in the respiratory microbiota of people with cystic fibrosis

Cited by 124 publications

References 106 publications

A Low-Molecular-Weight Alginate Oligosaccharide Disrupts Pseudomonal Microcolony Formation and Enhances Antibiotic Effectiveness

A Low-Molecular-Weight Alginate Oligosaccharide Disrupts Pseudomonal Microcolony Formation and Enhances Antibiotic Effectiveness

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

Plasticity of Candida albicans Biofilms

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