Potentiation of #imipenem by #relebactam for #Pseudomonas aeruginosa from #bacteraemia and respiratory infections (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Potentiation of imipenem by relebactam for Pseudomonas aeruginosa from bacteraemia and respiratory infections

Carolyne Horner, Shazad Mushtaq, David M Livermore, BSAC Resistance Surveillance Standing Committee

Journal of Antimicrobial Chemotherapy, dkz133, https://doi.org/10.1093/jac/dkz133

Published: 29 April 2019

 

Abstract

Background

Imipenem resistance in Pseudomonas aeruginosa most often entails loss of the ‘carbapenem-specific’ porin OprD; more rarely it reflects acquired carbapenemases. Loss of OprD only confers resistance to imipenem if AmpC β-lactamase is expressed, and we investigated whether this mechanism was overcome by relebactam, a developmental diazabicyclooctane β-lactamase inhibitor.

Methods

Consecutive P. aeruginosa isolates causing bacteraemia or hospital-onset lower respiratory tract infections were collected between 2014 and 2016 under the aegis of the BSAC Resistance Surveillance Programme. Imipenem MICs were determined centrally by BSAC agar dilution, with relebactam at a fixed concentration (4 mg/L).

Results

For most imipenem-susceptible P. aeruginosa (726/759, 95.7%), the MICs of imipenem alone were 0.5–2 mg/L and were decreased 3- to 4-fold by addition of relebactam, as based on geometric means or modes. For most imipenem-resistant P. aeruginosa (82/92, 89%), imipenem MICs were 8–16 mg/L, and were reduced to 1–2 mg/L by relebactam. These patterns applied regardless of whether the isolates were susceptible to penicillins and cephalosporins or had phenotypes suggesting derepressed AmpC or up-regulated efflux. Imipenem MICs for five P. aeruginosa with MBLs remained high (≥16 mg/L) regardless of relebactam.

Conclusions

Potentiation of imipenem by relebactam was almost universal, in accordance with the view that endogenous pseudomonal AmpC ordinarily protects against this carbapenem to a small degree. Imipenem MICs were reduced to the current breakpoint, or lower, except for MBL producers. Potentiation was not compromised by derepression of AmpC or up-regulation of efflux.

Issue Section: ORIGINAL RESEARCH

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Imipenem; Relebactam.

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#ESBLs and #resistance to #ceftazidime / #avibactam and #ceftolozane / #tazobactam combinations in #Escherichia coli and #Pseudomonas aeruginosa (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

ESBLs and resistance to ceftazidime/avibactam and ceftolozane/tazobactam combinations in Escherichia coli and Pseudomonas aeruginosa

José-Manuel Ortiz de la Rosa, Patrice Nordmann, Laurent Poirel

Journal of Antimicrobial Chemotherapy, dkz149, https://doi.org/10.1093/jac/dkz149

Published: 23 April 2019

 

Abstract

Objectives

To evaluate the efficacy of the recently launched β-lactam/β-lactamase inhibitor combinations ceftazidime/avibactam and ceftolozane/tazobactam against ESBL-producing Escherichia coli and Pseudomonas aeruginosa strains.

Methods

A series of ESBL-encoding genes (blaTEM, blaSHV, blaCTX-M, blaVEB, blaPER, blaGES and blaBEL) was cloned and expressed in E. coli or P. aeruginosa recipient strains. Cultures of E. coli TOP10 harbouring recombinant plasmids and therefore producing the different ESBLs tested were grown in order to perform measurements of catalytic activities, using benzylpenicillin, ceftazidime and ceftolozane as substrates. IC50s were additionally determined for clavulanic acid, tazobactam and avibactam.

Results

We showed here an overall better activity of ceftazidime/avibactam compared with ceftolozane/tazobactam toward ESBL-producing E. coli and P. aeruginosa. Several ESBLs of the GES, PER and BEL types conferred resistance to ceftolozane/tazobactam in E. coli and P. aeruginosa. For GES-6 and PER-1 producers, resistance to ceftolozane/tazobactam could be explained by a high hydrolysis of ceftolozane and a low activity of tazobactam as an inhibitor. On the other hand, PER-producing P. aeruginosa also exhibited resistance to ceftazidime/avibactam.

Conclusions

Altogether, the results show that the ESBL PER-1, which is widespread worldwide, may be a source of resistance to both ceftolozane/tazobactam and ceftazidime/avibactam. Excellent activity of ceftazidime/avibactam was highlighted for both ESBL-producing E. coli and ESBL-producing P. aeruginosa.

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; E. Coli; Pseudomonas aeruginosa; Ceftazidime; Avibactam; Ceftolozane; Tazobactam.

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Filamentous #bacteriophages are associated with chronic #Pseudomonas #lung #infections and #antibiotic resistance in #cysticfibrosis (Sci Transl Med., abstract)

[Source: Science Translational Medicine, full page: (LINK). Abstract, edited.]

Filamentous bacteriophages are associated with chronic Pseudomonas lung infections and antibiotic resistance in cystic fibrosis

Elizabeth B. Burgener1,*, Johanna M. Sweere2,3, Michelle S. Bach2, Patrick R. Secor4, Naomi Haddock3, Laura K. Jennings4, Rasmus L. Marvig5, Helle Krogh Johansen6,7, Elio Rossi6, Xiou Cao2, Lu Tian8, Laurence Nedelec9, Søren Molin10, Paul L. Bollyky2,3,† and Carlos E. Milla1,†

1 Center for Excellence in Pulmonary Biology, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA. 2 Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA. 3 Stanford Immunology, Stanford University, Stanford, CA 94305, USA. 4 Division of Biological Sciences, University of Montana, Missoula, MT 59812, USA. 5 Center for Genomic Medicine, Rigshospitalet–Copenhagen University Hospital, Copenhagen, Denmark. 6 Department of Clinical Microbiology, Rigshospitalet, Copenhagen Ø, Denmark. 7 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark. 8 Biomedical Data Science Administration and Statistics, Stanford University, Stanford, CA 94305, USA. 9 Primary Care and Population Health, Stanford University, Stanford, CA 94305, USA. 10 The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby, Denmark.

*Corresponding author. Email: eburgener@stanford.edu

† Co-senior authors.

Science Translational Medicine  17 Apr 2019: Vol. 11, Issue 488, eaau9748 / DOI: 10.1126/scitranslmed.aau9748

 

Infection-boosting phage

Chronic Pseudomonas aeruginosa infection is common in patients with cystic fibrosis (CF). Filamentous bacteriophage (Pf phage) can infect P. aeruginosa and has been shown to contribute to the virulence of infection in animal models. However, whether Pf phage plays a role in the pathogenicity of P. aeruginosa in CF is unknown. Now, Burgener et al. showed that Pf phage was abundantly expressed in sputum samples from two large cohorts of patients with CF. The presence of Pf phage was associated with increased antibiotic resistance and reduced lung function. The results suggest that Pf phage might play a role in the pathogenicity of P. aeruginosa infection in CF.

 

Abstract

Filamentous bacteriophage (Pf phage) contribute to the virulence of Pseudomonas aeruginosa infections in animal models, but their relevance to human disease is unclear. We sought to interrogate the prevalence and clinical relevance of Pf phage in patients with cystic fibrosis (CF) using sputum samples from two well-characterized patient cohorts. Bacterial genomic analysis in a Danish longitudinal cohort of 34 patients with CF revealed that 26.5% (n = 9) were consistently Pf phage positive. In the second cohort, a prospective cross-sectional cohort of 58 patients with CF at Stanford, sputum qPCR analysis showed that 36.2% (n = 21) of patients were Pf phage positive. In both cohorts, patients positive for Pf phage were older, and in the Stanford CF cohort, patients positive for Pf phage were more likely to have chronic P. aeruginosa infection and had greater declines in pulmonary function during exacerbations than patients negative for Pf phage presence in the sputum. Last, P. aeruginosa strains carrying Pf phage exhibited increased resistance to antipseudomonal antibiotics. Mechanistically, in vitro analysis showed that Pf phage sequesters these same antibiotics, suggesting that this mechanism may thereby contribute to the selection of antibiotic resistance over time. These data provide evidence that Pf phage may contribute to clinical outcomes in P. aeruginosa infection in CF.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
http://www.sciencemag.org/about/science-licenses-journal-article-reuse

This is an article distributed under the terms of the Science Journals Default License.

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Cystic fibrosis; Bacteriophages.

——

#Spanish nationwide #survey on #Pseudomonas aeruginosa #antimicrobial #resistance mechanisms and #epidemiology (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Spanish nationwide survey on Pseudomonas aeruginosa antimicrobial resistance mechanisms and epidemiology

Ester del Barrio-Tofiño, Laura Zamorano, Sara Cortes-Lara, Carla López-Causapé, Irina Sánchez-Diener, Gabriel Cabot, Germán Bou, Luis Martínez-Martínez, Antonio Oliver

Journal of Antimicrobial Chemotherapy, dkz147, https://doi.org/10.1093/jac/dkz147

Published: 15 April 2019

 

Abstract

Objectives

To undertake a Spanish nationwide survey on Pseudomonas aeruginosamolecular epidemiology and antimicrobial resistance.

Methods

Up to 30 consecutive healthcare-associated P. aeruginosa isolates collected in 2017 from each of 51 hospitals were studied. MICs of 13 antipseudomonal agents were determined by broth microdilution. Horizontally acquired β-lactamases were detected by phenotypic methods and PCR. Clonal epidemiology was evaluated through PFGE and MLST; at least one XDR isolate from each clone and hospital (n = 185) was sequenced.

Results

The most active antipseudomonals against the 1445 isolates studied were colistin and ceftolozane/tazobactam (both 94.6% susceptible, MIC50/90 = 1/2 mg/L) followed by ceftazidime/avibactam (94.2% susceptible, MIC50/90 = 2/8 mg/L). Up to 252 (17.3%) of the isolates were XDR. Carbapenemases/ESBLs were detected in 3.1% of the isolates, including VIM, IMP, GES, PER and OXA enzymes. The most frequent clone among the XDR isolates was ST175 (40.9%), followed by CC235 (10.7%), ST308 (5.2%) and CC111 (4.0%). Carbapenemase production varied geographically and involved diverse clones, including 16.5% of ST175 XDR isolates. Additionally, 56% of the sequenced XDR isolates showed horizontally acquired aminoglycoside-modifying enzymes, which correlated with tobramycin resistance. Two XDR isolates produced QnrVC1, but fluoroquinolone resistance was mostly caused by QRDR mutations. Beyond frequent mutations (>60%) in OprD and AmpC regulators, four isolates showed AmpC mutations associated with resistance to ceftolozane/tazobactam and ceftazidime/avibactam.

Conclusions

ST175 is the most frequent XDR high-risk clone in Spanish hospitals, but this nationwide survey also indicates a complex scenario in which major differences in local epidemiology, including carbapenemase production, need to be acknowledged in order to guide antimicrobial therapy.

Topic: phenotype – polymerase chain reaction – pseudomonas aeruginosa – mutation – colistin – epidemiology – ceftazidime – clone cells – drug resistance, microbial – electrophoresis, gel, pulsed-field – epidemiology, molecular – fluoroquinolones – spain – enzymes – tobramycin – aminoglycosides – antimicrobials – tazobactam – extended-spectrum beta lactamases – malnutrition-inflammation-cachexia syndrome – ceftolozane – avibactam

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Spain; Colistin; Ceftazidime; Fluoroquinolones; Tobramycin; Aminoglycosides; Tazobactam; Avibactam.

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#Lysocins: Bioengineered #Antimicrobials that Deliver #Lysins Across the Outer Membrane of Gram-Negative #Bacteria (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Lysocins: Bioengineered Antimicrobials that Deliver Lysins Across the Outer Membrane of Gram-Negative Bacteria

Ryan D. Heselpoth, Chad W. Euler, Raymond Schuch, Vincent A. Fischetti

DOI: 10.1128/AAC.00342-19

 

ABSTRACT

The prevalence of multidrug-resistant Pseudomonas aeruginosa has stimulated development of alternative therapeutics. Bacteriophage peptidoglycan hydrolases, termed lysins, represent an emerging antimicrobial option for targeting Gram-positive bacteria. However, lysins against Gram-negatives are generally deterred by the outer membrane and their inability to work in serum. One solution involves exploiting evolved delivery systems used by colicin-like bacteriocins (e.g., S-type pyocins of P. aeruginosa) to translocate through the outer membrane. Following surface receptor binding, colicin-like bacteriocins form Tol- or TonB-dependent translocons to actively import cytotoxic domains through outer membrane protein channels. With this understanding, we developed lysocins, which are bioengineered lysin-bacteriocinfusion molecules capable of periplasmic import. In our proof of concept studies, components from the P. aeruginosa bacteriocin pyocin S2 responsible for surface receptor binding and outer membrane translocation were fused to the GN4 lysin to generate the PyS2-GN4 lysocin. PyS2-GN4 delivered the GN4 lysin to the periplasm to induce peptidoglycan cleavage and log-fold P. aeruginosa death with minimal endotoxin release. While displaying narrow-spectrum antipseudomonal activity in human serum, PyS2-GN4 also efficiently disrupted biofilms, outperformed standard of care antibiotics, exhibited no cytotoxicity towards eukaryotic cells, and protected mice from P. aeruginosa challenge in a bacteremia model. In addition to P. aeruginosa, lysocins can be constructed to target other prominent Gram-negative bacterial pathogens.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Bacteriophages; Lysins; Bacteriocins; Lysocins.

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#Pseudomonas aeruginosa stimulates nuclear sphingosine-1-phosphate generation and epigenetic regulation of #lung inflammatory #injury (Thorax, abstract)

[Source: Thorax, full page: (LINK). Abstract, edited.]

Pseudomonas aeruginosa stimulates nuclear sphingosine-1-phosphate generation and epigenetic regulation of lung inflammatory injury

David L Ebenezer1, Evgeny V Berdyshev2, Irina A Bronova2, Yuru Liu3, Chinnaswamy Tiruppathi3, Yulia Komarova3, Elizaveta V Benevolenskaya1, Vidyani Suryadevara4, Alison W Ha1, Anantha Harijith5, Rubin M Tuder6, Viswanathan Natarajan3,4, Panfeng Fu3

Author affiliations: {1} Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois, USA; {2} Department of Medicine, National Jewish Health, Denver, Colorado, USA; {3} Department of Pharmacology, University of Illinois, Chicago, Illinois, USA; {4} Department of Medicine, University of Illinois, Chicago, Illinois, USA; {5} Department of Pediatrics, University of Illinois, Chicago, Illinois, USA; {6} Department of Medicine, University of Colorado, Denver, Colorado, USA

Correspondence to Dr Viswanathan Natarajan and Dr Panfeng Fu, Department of Pharmacology, University of Illinois, Chicago IL 60612, USA; visnatar@uic.edu, pfu@uic.edu

 

Abstract

Introduction 

Dysregulated sphingolipid metabolism has been implicated in the pathogenesis of various pulmonary disorders. Nuclear sphingosine-1-phosphate (S1P) has been shown to regulate histone acetylation, and therefore could mediate pro-inflammatory genes expression.

Methods 

Profile of sphingolipid species in bronchoalveolar lavage fluids and lung tissue of mice challenged with Pseudomonas aeruginosa (PA) was investigated. The role of nuclear sphingosine kinase (SPHK)2 and S1P in lung inflammatory injury by PA using genetically engineered mice was determined.

Results 

Genetic deletion of Sphk2, but not Sphk1, in mice conferred protection from PA-mediated lung inflammation. PA infection stimulated phosphorylation of SPHK2 and its localisation in epithelial cell nucleus, which was mediated by protein kinase C (PKC) δ. Inhibition of PKC δ or SPHK2 activity reduced PA-mediated acetylation of histone H3 and H4, which was necessary for the secretion of pro-inflammatory cytokines, interleukin-6 and tumour necrosis factor-α. The clinical significance of the findings is supported by enhanced nuclear localisation of p-SPHK2 in the epithelium of lung specimens from patients with cystic fibrosis (CF).

Conclusions 

Our studies define a critical role for nuclear SPHK2/S1P signalling in epigenetic regulation of bacterial-mediated inflammatory lung injury. Targeting SPHK2 may represent a potential strategy to reduce lung inflammatory pulmonary disorders such as pneumonia and CF.

___

DOI: http://dx.doi.org/10.1136/thoraxjnl-2018-212378

 

Footnotes

VN and PF contributed equally.

Contributors 

PF, DLE, VN, CT, YK, and EVB designed the research; DLE, EVB, IAB, VS, AWH, AH, RMT and VN performed the experiments; VN, DLE and PF analyzed the data and wrote the manuscript.

Funding 

This work was partly supported by the US National Institutes of Health grant P01 Hl09850 to VN.

Competing interests 

None declared.

Ethics approval 

This study was approved by the University of Colorado Institutional Review Board.

Provenance and peer review 

Not commissioned; externally peer reviewed.

Correction notice 

This article has been corrected since it was published Online First. A correction was made to Figure 4.

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Keywords: Pseudomonas aeruginosa; Pneumonia; Acute Lung Injury.

——

#Geographical and temporal #variation in the #frequency and #antimicrobial susceptibility of #bacteria isolated from patients hospitalized with bacterial #pneumonia: results from 20 years of the #SENTRY… (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Geographical and temporal variation in the frequency and antimicrobial susceptibility of bacteria isolated from patients hospitalized with bacterial pneumonia: results from 20 years of the SENTRY Antimicrobial Surveillance Program (1997–2016)

Helio S Sader, Mariana Castanheira, S J Ryan, Arends Herman Goossens, Robert K Flamm

Journal of Antimicrobial Chemotherapy, dkz074, https://doi.org/10.1093/jac/dkz074

Published:  06 March 2019

 

Abstract

Background

The SENTRY Antimicrobial Surveillance Program monitors the frequency of occurrence and antimicrobial susceptibility of organisms from various infection types worldwide.

Methods

A total of 102 995 bacterial isolates were consecutively collected (one per patient) in 1997–2016 from 258 medical centres in North America (n = 44 999; 113 centres), Europe (n = 30 988; 61 centres from 22 nations), the Asia-Pacific region (APAC; n = 16 503; 67 centres from 12 nations) and Latin America (n = 10 505; 17 centres from 7 nations). Organisms were isolated from respiratory tract specimens and tested for susceptibility by broth microdilution methods in a central laboratory.

Results

Staphylococcus aureus (n = 24 351) and Pseudomonas aeruginosa (n = 22 279) were the most common organisms overall. Klebsiella spp. (n = 10 565) ranked third in North America, Europe and APAC. The proportion of Gram-negatives increased from 70.0%–74.7% to 80.9%–82.6% in Europe, APAC and Latin America, and remained stable (65.5%–66.1%) in North America. Methicillin resistance rates decreased substantially in all four regions from 2005–06 to 2015–16 among S. aureus isolates. P. aeruginosa susceptibility to meropenem decreased overall in the initial years, but increased in the last years of the investigation. Among Klebsiella spp. isolates, susceptibility to ceftriaxone/meropenem decreased from 85.9%/99.3% to 58.6%/85.8% in Europe and from 91.8%/99.5% to 81.6%/93.9% in APAC during the study period.

Conclusions

Rank order and susceptibility rates varied widely by geographical region and over time. The occurrence of some resistance phenotypes increased, though others decreased over the 20 years of the SENTRY Antimicrobial Surveillance Program.

Topic:  phenotype – pseudomonas aeruginosa – ceftriaxone – staphylococcus aureus – bacterial pneumonia – asia – geographic area – inpatients – klebsiella – latin america – respiratory system – infection – bacteria – meropenem – antimicrobials – antimicrobial susceptibility – surveillance program

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Meropenem; Ceftriaxone; MRSA; Klebsiella pneumoniae; Pseudomonas aeruginosa; Pneumonia.

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