Remodeling of pSK1 Family Plasmids and Enhanced Chlorhexidine Tolerance in a Dominant Hospital Lineage of Methicillin-ResistantStaphylococcus aureus

ABSTRACTStaphylococcus aureusis a significant human pathogen whose evolution and adaptation have been shaped in part by mobile genetic elements (MGEs), facilitating the global spread of extensive antimicrobial resistance. However, our understanding of the evolutionary dynamics surrounding MGEs, in particular, how changes in the structure of multidrug resistance (MDR) plasmids may influence important staphylococcal phenotypes, is incomplete. Here, we undertook a population and functional genomics study of 212 methicillin-resistantS. aureus(MRSA) sequence type 239 (ST239) isolates collected over 32 years to explore the evolution of the pSK1 family of MDR plasmids, illustrating how these plasmids have coevolved with and contributed to the successful adaptation of this persistent MRSA lineage. Using complete genomes and temporal phylogenomics, we reconstructed the evolution of the pSK1 family lineage from its emergence in the late 1970s and found that multiple structural variants have arisen. Plasmid maintenance and stability were linked to IS256- and IS257-mediated chromosomal integration and disruption of the plasmid replication machinery. Overlaying genomic comparisons with phenotypic susceptibility data for gentamicin, trimethoprim, and chlorhexidine, it appeared that pSK1 has contributed to enhanced resistance in ST239 MRSA isolates through two mechanisms: (i) acquisition of plasmid-borne resistance mechanisms increasing the rates of gentamicin resistance and reduced chlorhexidine susceptibility and (ii) changes in the plasmid configuration linked with further enhancement of chlorhexidine tolerance. While the exact mechanism of enhanced tolerance remains elusive, this research has uncovered a potential evolutionary response of ST239 MRSA to biocides, one of which may contribute to the ongoing persistence and adaptation of this lineage within health care institutions.

Download Full-text

Remodelling of pSK1 Family Plasmids and Enhanced Chlorhexidine Tolerance in Methicillin-ResistantStaphylococcus aureus

10.1101/457838 ◽

2018 ◽

Author(s):

Sarah L Baines ◽

Slade O Jensen ◽

Neville Firth ◽

Anders Gonçalves da Silva ◽

Torsten Seemann ◽

...

Keyword(s):

Evolutionary Dynamics ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Structural Variants ◽

Susceptibility Data ◽

Enhanced Resistance ◽

Evolutionary Response ◽

Global Spread ◽

Gentamicin Resistance ◽

Phenotypic Susceptibility

AbstractStaphylococcus aureusis a significant human pathogen whose evolution and adaptation has been shaped in part by mobile genetic elements (MGEs), facilitating global spread of extensive antimicrobial resistance. However, our understanding of the evolutionary dynamics surrounding MGEs is incomplete, in particular how changes in the structure of multidrug-resistant (MDR) plasmids may influence important staphylococcal phenotypes. Here, we undertook a population-and functional-genomics study of 212 methicillin-resistantS. aureus(MRSA) ST239 isolates collected over 32 years to explore the evolution of the pSK1 family of MDR plasmids, illustrating how these plasmids have co-evolved with and contributed to the successful adaptation of this persistent MRSA lineage. Using complete genomes and temporal phylogenomics we reconstructed the evolution of the pSK1 family lineage from its emergence in the late 1970s, with multiple structural variants arising. Plasmid maintenance and stability was linked to IS256- and IS257-mediated chromosomal integration and disruption of plasmid replication machinery. Overlaying genomic comparisons with phenotypic susceptibility data for gentamicin and chlorhexidine, it appeared that pSK1 has contributed to enhanced resistance in ST239 MRSA through two mechanisms: (i) acquisition of plasmid-borne resistance mechanisms increasing rates of gentamicin resistance and reduced chlorhexidine susceptibility, and (ii) changes in plasmid configuration linked with further enhancement of chlorhexidine tolerance. While the exact mechanism of enhanced tolerance remains elusive, this research has uncovered a clear evolutionary response of ST239 MRSA to chlorhexidine, one which may contribute to the ongoing persistence and adaptation of this lineage within healthcare institutions.

Download Full-text

The Resistome of Pseudomonas aeruginosa in Relationship to Phenotypic Susceptibility

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03954-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 427-436 ◽

Cited By ~ 135

Author(s):

Veronica N. Kos ◽

Maxime Déraspe ◽

Robert E. McLaughlin ◽

James D. Whiteaker ◽

Paul H. Roy ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Genetic Determinants ◽

Content Type ◽

Susceptibility Data ◽

Next Generation Sequencing Ngs ◽

Sequence Types ◽

Generation Sequencing ◽

Phenotypic Susceptibility

ABSTRACTMany clinical isolates ofPseudomonas aeruginosacause infections that are difficult to eradicate due to their resistance to a wide variety of antibiotics. Key genetic determinants of resistance were identified through genome sequences of 390 clinical isolates ofP. aeruginosa, obtained from diverse geographic locations collected between 2003 and 2012 and were related to microbiological susceptibility data for meropenem, levofloxacin, and amikacin. β-Lactamases and integron cassette arrangements were enriched in the established multidrug-resistant lineages of sequence types ST111 (predominantly O12) and ST235 (O11). This study demonstrates the utility of next-generation sequencing (NGS) in defining relevant resistance elements and highlights the diversity of resistance determinants withinP. aeruginosa. This information is valuable in furthering the design of diagnostics and therapeutics for the treatment ofP. aeruginosainfections.

Download Full-text

Different evolutionary trends form the twilight zone of the bacterial pan-genome

Microbial Genomics ◽

10.1099/mgen.0.000670 ◽

2021 ◽

Vol 7 (9) ◽

Author(s):

Gal Horesh ◽

Alyce Taylor-Brown ◽

Stephanie McGimpsey ◽

Florent Lassalle ◽

Jukka Corander ◽

...

Keyword(s):

Population Structure ◽

Evolutionary Dynamics ◽

Bacterial Species ◽

Resistance Mechanisms ◽

Content Type ◽

Pan Genome ◽

Metabolic Versatility ◽

Species Population ◽

Genome Analyses ◽

Uneven Sampling

The pan-genome is defined as the combined set of all genes in the gene pool of a species. Pan-genome analyses have been very useful in helping to understand different evolutionary dynamics of bacterial species: an open pan-genome often indicates a free-living lifestyle with metabolic versatility, while closed pan-genomes are linked to host-restricted, ecologically specialized bacteria. A detailed understanding of the species pan-genome has also been instrumental in tracking the phylodynamics of emerging drug resistance mechanisms and drug-resistant pathogens. However, current approaches to analyse a species’ pan-genome do not take the species population structure into account, nor do they account for the uneven sampling of different lineages, as is commonplace due to over-sampling of clinically relevant representatives. Here we present the application of a population structure-aware approach for classifying genes in a pan-genome based on within-species distribution. We demonstrate our approach on a collection of 7500 Escherichia coli genomes, one of the most-studied bacterial species and used as a model for an open pan-genome. We reveal clearly distinct groups of genes, clustered by different underlying evolutionary dynamics, and provide a more biologically informed and accurate description of the species’ pan-genome.

Download Full-text

Further data on the acute effect of intravenous steroids on canine CSF secretion and absorption

Journal of Neurosurgery ◽

10.3171/jns.1979.50.4.0477 ◽

1979 ◽

Vol 50 (4) ◽

pp. 477-482 ◽

Cited By ~ 15

Author(s):

A. Richard Vela ◽

Michael E. Carey ◽

Bruce M. Thompson

Keyword(s):

Acute Effect ◽

Resistance Mechanisms ◽

Outflow Resistance ◽

Intravenous Methylprednisolone ◽

Content Type ◽

Difference Of Opinion ◽

Ventriculocisternal Perfusion ◽

Intravenous Steroids ◽

Csf Production ◽

Csf Absorption

✓ Considerable difference of opinion has arisen as to whether intravenously administered steroids affect cerebrospinal fluid (CSF) production in the acute laboratory animal undergoing ventriculocisternal perfusion. Our experiments with ventriculocisternal perfusion in dogs indicate that, when given intravenously, neither dexamethasone, methylprednisolone, hydrocortisone, nor aldosterone result in a significant, acute effect upon CSF production. Similarly, CSF absorption and outflow resistance mechanisms are not acutely affected by intravenous methylprednisolone, hydrocortisone, and aldosterone. Dexamethasone also probably does not produce an immediate effect upon CSF absorption.

Download Full-text

Multicenter Clinical and Molecular Epidemiological Analysis of Bacteremia Due to Carbapenem-Resistant Enterobacteriaceae (CRE) in the CRE Epicenter of the United States

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02349-16 ◽

2017 ◽

Vol 61 (4) ◽

Cited By ~ 98

Author(s):

Michael J. Satlin ◽

Liang Chen ◽

Gopi Patel ◽

Angela Gomez-Simmonds ◽

Gregory Weston ◽

...

Keyword(s):

New York ◽

Empirical Therapy ◽

Carbapenem Resistance ◽

The United States ◽

Resistance Mechanisms ◽

Rapid Diagnostics ◽

Multicenter Studies ◽

Content Type ◽

Medical Centers ◽

Carbapenem Resistant

ABSTRACT Although the New York/New Jersey (NY/NJ) area is an epicenter for carbapenem-resistant Enterobacteriaceae (CRE), there are few multicenter studies of CRE from this region. We characterized patients with CRE bacteremia in 2013 at eight NY/NJ medical centers and determined the prevalence of carbapenem resistance among Enterobacteriaceae bloodstream isolates and CRE resistance mechanisms, genetic backgrounds, capsular types (cps), and antimicrobial susceptibilities. Of 121 patients with CRE bacteremia, 50% had cancer or had undergone transplantation. The prevalences of carbapenem resistance among Klebsiella pneumoniae, Enterobacter spp., and Escherichia coli bacteremias were 9.7%, 2.2%, and 0.1%, respectively. Ninety percent of CRE were K. pneumoniae and 92% produced K. pneumoniae carbapenemase (KPC-3, 48%; KPC-2, 44%). Two CRE produced NDM-1 and OXA-48 carbapenemases. Sequence type 258 (ST258) predominated among KPC-producing K. pneumoniae (KPC-Kp). The wzi154 allele, corresponding to cps-2, was present in 93% of KPC-3-Kp, whereas KPC-2-Kp had greater cps diversity. Ninety-nine percent of CRE were ceftazidime-avibactam (CAZ-AVI)-susceptible, although 42% of KPC-3-Kp had an CAZ-AVI MIC of ≥4/4 μg/ml. There was a median of 47 h from bacteremia onset until active antimicrobial therapy, 38% of patients had septic shock, and 49% died within 30 days. KPC-3-Kp bacteremia (adjusted odds ratio [aOR], 2.58; P = 0.045), cancer (aOR, 3.61, P = 0.01), and bacteremia onset in the intensive care unit (aOR, 3.79; P = 0.03) were independently associated with mortality. Active empirical therapy and combination therapy were not associated with survival. Despite a decade of experience with CRE, patients with CRE bacteremia have protracted delays in appropriate therapies and high mortality rates, highlighting the need for rapid diagnostics and evaluation of new therapeutics.

Download Full-text

Learning from the biology of evolution: exaptation as a design strategy for future cities

Smart and Sustainable Built Environment ◽

10.1108/sasbe-08-2021-0141 ◽

2022 ◽

Vol ahead-of-print (ahead-of-print) ◽

Author(s):

Alessandro Melis ◽

Jose Antonio Lara-Hernandez ◽

Barbora Melis

Keyword(s):

Design Methodology ◽

Evolutionary Dynamics ◽

Design Strategy ◽

Structural Redundancy ◽

Global Crisis ◽

Content Type ◽

Creative Systems ◽

Functional Shift

PurposeThis paper highlights the importance of transdisciplinary studies in times of crisis. In the first part, the study shows the benefits of the introduction of literature on biology to better understand the evolutionary dynamics of architecture.Design/methodology/approachThe focus of the research concerns architectural exaptation. In biology, exaptation is a functional shift of a structure that already had a prior but different function. We will also learn that, in biology, all creative systems are redundant and involve variability and diversity.FindingsAs a conclusion, through the comparison between biology and architecture, we will, therefore, try to build an architectural taxonomy that demonstrates how indeterminism is not a subcategory of design. Instead, design paradigms in which redundancy and variable diversity of structures reflect functionalism constitute an equivalent and essential complement with respect to design determinism.Originality/valueIt demonstrates how architectural exaptation, intended as an indeterministic and radical mode of design, can contribute to overcoming the current global crisis because structural redundancy is frequently functional, mostly in ever-changing and unstable environments. For instance, the failure of a planned function of a city can be an opportunity to re-use a structure designed for an obsolete function to respond to unexpected constraints.

Download Full-text

Resistance to nitrofurantoin is an indicator of extensive drug-resistant (XDR) Enterobacteriaceae

Journal of Medical Microbiology ◽

10.1099/jmm.0.001347 ◽

2021 ◽

Vol 70 (4) ◽

Author(s):

Balaram Khamari ◽

Prakash Kumar ◽

Bulagonda Eswarappa Pradeep

Keyword(s):

Antimicrobial Agents ◽

Efflux Pump ◽

Treatment Options ◽

Strong Association ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Resistant Bacteria ◽

Drug Resistant ◽

Content Type ◽

Link Type

Introduction. Nitrofurantoin is one of the preferred antibiotics in the treatment of uropathogenic multidrug-resistant (MDR) infections. However, resistance to nitrofurantoin in extensively drug-resistant (XDR) bacteria has severely limited the treatment options. Gap statement. Information related to co-resistance or collateral sensitivity (CS) with reference to nitrofurantoin resistant bacteria is limited. Aim. To study the potential of nitrofurantoin resistance as an indicator of the XDR phenotype in Enterobacteriaceae . Methods. One hundred (45 nitrofurantoin-resistant, 21 intermediately resistant and 34 nitrofurantoin-susceptible) Enterobacteriaceae were analysed in this study. Antibiotic susceptibility testing (AST) against nitrofurantoin and 17 other antimicrobial agents across eight different classes was performed by using the Vitek 2.0 system. The isolates were screened for the prevalence of acquired antimicrobial resistance (AMR) and efflux pump genes by PCR. Results. In total, 51 % of nitrofurantoin-resistant and 28 % of intermediately nitrofurantoin resistant isolates exhibited XDR characteristics, while only 3 % of nitrofurantoin-sensitive isolates were XDR (P=0.0001). Significant co-resistance was observed between nitrofurantoin and other tested antibiotics (β-lactam, cephalosporin, carbapenem, aminoglycoside and tetracycline). Further, the prevalence of AMR and efflux pump genes was higher in the nitrofurantoin-resistant strains compared to the susceptible isolates. A strong association was observed between nitrofurantoin resistance and the presence of bla PER-1, bla NDM-1, bla OXA-48, ant(2) and oqxA-oqxB genes. Tigecycline (84 %) and colistin (95 %) were the only antibiotics to which the majority of the isolates were susceptible. Conclusion. Nitrofurantoin resistance could be an indicator of the XDR phenotype among Enterobacteriaceae , harbouring multiple AMR and efflux pump genes. Tigecycline and colistin are the only antibiotics that could be used in the treatment of such XDR infections. A deeper understanding of the co-resistance mechanisms in XDR pathogens and prescription of AST-based appropriate combination therapy may help mitigate this problem.

Download Full-text

Evolution of a predator-induced, nonlinear reaction norm

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2017.0859 ◽

2017 ◽

Vol 284 (1861) ◽

pp. 20170859 ◽

Cited By ~ 7

Author(s):

Mauricio J. Carter ◽

Martin I. Lind ◽

Stuart R. Dennis ◽

William Hentley ◽

Andrew P. Beckerman

Keyword(s):

Evolutionary Dynamics ◽

Daphnia Pulex ◽

Reaction Norm ◽

Maximum Response ◽

Selective Predation ◽

Evolutionary Trajectory ◽

Defensive Reaction ◽

Selection Gradients ◽

Hunting Strategies ◽

Evolutionary Response

Inducible, anti-predator traits are a classic example of phenotypic plasticity. Their evolutionary dynamics depend on their genetic basis, the historical pattern of predation risk that populations have experienced and current selection gradients. When populations experience predators with contrasting hunting strategies and size preferences, theory suggests contrasting micro-evolutionary responses to selection. Daphnia pulex is an ideal species to explore the micro-evolutionary response of anti-predator traits because they face heterogeneous predation regimes, sometimes experiencing only invertebrate midge predators and other times experiencing vertebrate fish and invertebrate midge predators. We explored plausible patterns of adaptive evolution of a predator-induced morphological reaction norm. We combined estimates of selection gradients that characterize the various habitats that D. pulex experiences with detail on the quantitative genetic architecture of inducible morphological defences. Our data reveal a fine scale description of daphnid defensive reaction norms, and a strong covariance between the sensitivity to cues and the maximum response to cues. By analysing the response of the reaction norm to plausible, predator-specific selection gradients, we show how in the context of this covariance, micro-evolution may be more uniform than predicted from size-selective predation theory. Our results show how covariance between the sensitivity to cues and the maximum response to cues for morphological defence can shape the evolutionary trajectory of predator-induced defences in D. pulex .

Download Full-text

In VitroSpectrum of Pexiganan Activity When Tested against Pathogens from Diabetic Foot Infections and with Selected Resistance Mechanisms

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04773-14 ◽

2015 ◽

Vol 59 (3) ◽

pp. 1751-1754 ◽

Cited By ~ 30

Author(s):

Robert K. Flamm ◽

Paul R. Rhomberg ◽

Katie M. Simpson ◽

David J. Farrell ◽

Helio S. Sader ◽

...

Keyword(s):

Diabetic Foot ◽

Antimicrobial Agents ◽

Resistance Mechanisms ◽

Surveillance Program ◽

Content Type ◽

Diabetic Foot Infections ◽

Antimicrobial Surveillance ◽

Mueller Hinton ◽

The Family ◽

Infection Types

ABSTRACTPexiganan, a 22-amino-acid synthetic cationic peptide, is currently in phase 3 clinical trials as a topical antimicrobial agent for the treatment of mild infections associated with diabetic foot ulcers. Bacterial isolates from the 2013 SENTRY Antimicrobial Surveillance Program designated as pathogens from diabetic foot infections (DFI) and Gram-negative and -positive pathogens from various infection types that harbored selected resistance mechanisms/phenotypes were tested against pexiganan in reference cation-adjusted Mueller-Hinton broth. The MIC50and MIC90against all organisms tested from DFI were 16 and 32 μg/ml, respectively.Escherichia coli,Klebsiella pneumoniae,Citrobacter koseri,Enterobacter cloacae,Acinetobacterspecies, andPseudomonas aeruginosaMIC values ranged from 8 to 16 μg/ml. Pexiganan MIC values amongStaphylococcus aureus(methicillin-resistantS. aureus[MRSA] and methicillin-susceptibleS. aureus[MSSA]), beta-hemolytic streptococci, andEnterococcus faeciumranged from 8 to 32 μg/ml. Pexiganan activity was not adversely affected for members of the familyEnterobacteriaceaeorP. aeruginosathat produced β-lactamases or resistance mechanisms to other commonly used antimicrobial agents. Decreased susceptibility to vancomycin did not affect pexiganan activity againstS. aureusorE. faecium.Enterococcus faecalisappears to be intrinsically less susceptible to pexiganan (MIC, 32 to 256 μg/ml). The “all organism” MIC90of 32 μg/ml for pexiganan in this study was >250-fold below the pexiganan concentration in the cream/delivery vehicle being developed for topical use.

Download Full-text

Antimicrobial Susceptibility to Azithromycin among Salmonella enterica Isolates from the United States

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00590-11 ◽

2011 ◽

Vol 55 (9) ◽

pp. 3985-3989 ◽

Cited By ~ 49

Author(s):

Maria Sjölund-Karlsson ◽

Kevin Joyce ◽

Karen Blickenstaff ◽

Takiyah Ball ◽

Jovita Haro ◽

...

Keyword(s):

United States ◽

Antimicrobial Susceptibility ◽

Salmonella Enterica ◽

Antimicrobial Agents ◽

The United States ◽

Outcome Data ◽

Content Type ◽

Susceptibility Data ◽

Retail Meat ◽

Clinical Breakpoints

ABSTRACTDue to emerging resistance to traditional antimicrobial agents, such as ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol, azithromycin is increasingly used for the treatment of invasiveSalmonellainfections. In the present study, 696 isolates of non-TyphiSalmonellacollected from humans, food animals, and retail meats in the United States were investigated for antimicrobial susceptibility to azithromycin. Seventy-twoSalmonella entericaserotype Typhi isolates from humans were also tested. For each isolate, MICs of azithromycin and 15 other antimicrobial agents were determined by broth microdilution. Among the non-TyphiSalmonellaisolates, azithromycin MICs among human isolates ranged from 1 to 32 μg/ml, whereas the MICs among the animal and retail meat isolates ranged from 2 to 16 μg/ml and 4 to 16 μg/ml, respectively. AmongSalmonellaserotype Typhi isolates, the azithromycin MICs ranged from 4 to 16 μg/ml. The highest MIC observed in the present study was 32 μg/ml, and it was detected in three human isolates belonging to serotypes Kentucky, Montevideo, and Paratyphi A. Based on our findings, we propose an epidemiological cutoff value (ECOFF) for wild-typeSalmonellaof ≤16 μg/ml of azithromycin. The susceptibility data provided could be used in combination with clinical outcome data to determine tentative clinical breakpoints for azithromycin andSalmonella enterica.

Download Full-text