scholarly journals Pseudomonas aeruginosa fosfomycin resistance mechanisms affect non-inherited fluoroquinolone tolerance

2011 ◽  
Vol 60 (3) ◽  
pp. 329-336 ◽  
Author(s):  
Valerie N. De Groote ◽  
Maarten Fauvart ◽  
Cyrielle I. Kint ◽  
Natalie Verstraeten ◽  
Ann Jans ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Wide Spectrum ◽  
Acquired Resistance ◽  
Opportunistic Pathogen ◽  
Resistance Mechanisms ◽  
Clinical Settings ◽  
Persister Cells ◽  
Similar Phenotype ◽  
Fosfomycin Resistance ◽  
High Concentrations

Pseudomonas aeruginosa is an opportunistic pathogen that poses a threat in clinical settings due to its intrinsic and acquired resistance to a wide spectrum of antibiotics. Additionally, the presence of a subpopulation of cells surviving high concentrations of antibiotics, called persisters, makes it virtually impossible to eradicate a chronic infection. The mechanism underlying persistence is still unclear, partly due to the fact that it is a non-inherited phenotype. Based on our findings from a previously performed screening effort for P. aeruginosa persistence genes, we hypothesize that crosstalk can occur between two clinically relevant mechanisms: the persistence phenomenon and antibiotic resistance. This was tested by determining the persistence phenotype of P. aeruginosa strains that are resistant to the antibiotic fosfomycin due to either of two unrelated fosfomycin resistance mechanisms. Overexpression of fosA (PA1129) confers fosfomycin resistance by enzymic modification of the antibiotic, and in addition causes a decrease in the number of persister cells surviving ofloxacin treatment. Both phenotypes require the enzymic function of FosA, as mutation of the Arg119 residue abolishes fosfomycin resistance as well as low persistence. The role for fosfomycin resistance mechanisms in persistence is corroborated by demonstrating a similar phenotype in a strain with a mutation in glpT (PA5235), which encodes a glycerol-3-phosphate transporter essential for fosfomycin uptake. These results indicate that fosfomycin resistance, conferred by glpT mutation or by overexpression of fosA, results in a decrease in the number of persister cells after treatment with ofloxacin and additionally stress that further research into the interplay between fosfomycin resistance and persistence is warranted.

Differences in fosfomycin resistance mechanisms between Pseudomonas aeruginosa and Enterobacterales

2021 ◽  
Author(s):  
Dina Zheng ◽  
Phillip J. Bergen ◽  
Cornelia B. Landersdorfer ◽  
Elizabeth B. Hirsch
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acquired Resistance ◽  
Drug Approval ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Supporting Evidence ◽  
E Coli ◽  
Fosfomycin Resistance ◽  
The 1960S ◽  
Tract Infections

Multidrug-resistant (MDR) Pseudomonas aeruginosa presents a serious threat to public health due to its widespread resistance to numerous antibiotics. P. aeruginosa commonly causes nosocomial infections including urinary tract infections (UTI) which have become increasingly difficult to treat. The lack of effective therapeutic agents has renewed interest in fosfomycin, an old drug discovered in the 1960s and approved prior to the rigorous standards now required for drug approval. Fosfomycin has a unique structure and mechanism of action, making it a favorable therapeutic alternative for MDR pathogens that are resistant to other classes of antibiotics. The absence of susceptibility breakpoints for fosfomycin against P. aeruginosa limits its clinical use and interpretation due to extrapolation of breakpoints established for Escherichia coli or Enterobacterales without supporting evidence. Furthermore, fosfomycin use and efficacy for treatment of P. aeruginosa is also limited by both inherent and acquired resistance mechanisms. This narrative review provides an update on currently identified resistance mechanisms to fosfomycin, with a focus on those mediated by P. aeruginosa such as peptidoglycan recycling enzymes, chromosomal Fos enzymes, and transporter mutation. Additional fosfomycin resistance mechanisms exhibited by Enterobacterales including mutations in transporters and associated regulators, plasmid mediated Fos enzymes, kinases, and murA modification, are also summarized and contrasted. These data highlight that different fosfomycin resistance mechanisms may be associated with elevated MIC values in P. aeruginosa compared to Enterobacterales, emphasizing that extrapolation of E. coli breakpoints to P. aeruginosa should be avoided.

scholarly journals Resistance Mechanisms of Multiresistant Pseudomonas aeruginosa Strains from Germany and Correlation with Hypermutation

2007 ◽  
Vol 51 (11) ◽  
pp. 4062-4070 ◽  
Author(s):  
B. Henrichfreise ◽  
I. Wiegand ◽  
W. Pfister ◽  
B. Wiedemann
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Type Ii ◽  
Mechanisms Of Resistance ◽  
Resistance Determinants ◽  
Class 1 ◽  
Mutator Strains ◽  
Multiresistant Strains

ABSTRACT In this study, we analyzed the mechanisms of multiresistance for 22 clinical multiresistant and clonally different Pseudomonas aeruginosa strains from Germany. Twelve and 10 strains originated from cystic fibrosis (CF) and non-CF patients, respectively. Overproduction of the efflux systems MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM was studied. Furthermore, loss of OprD, alterations in type II topoisomerases, AmpC overproduction, and the presence of 25 acquired resistance determinants were investigated. The presence of a hypermutation phenotype was also taken into account. Besides modifications in GyrA (91%), the most frequent mechanisms of resistance were MexXY-OprM overproduction (82%), OprD loss (82%), and AmpC overproduction (73%). Clear differences between strains from CF and non-CF patients were found: numerous genes coding for aminoglycoside-modifying enzymes and located, partially in combination with β-lactamase genes, in class 1 integrons were found only in strains from non-CF patients. Furthermore, multiple modifications in type II topoisomerases conferring high quinolone resistance levels and overexpression of MexAB-OprM were exclusively detected in multiresistant strains from non-CF patients. Correlations of the detected phenotypes and resistance mechanisms revealed a great impact of efflux pump overproduction on multiresistance in P. aeruginosa. Confirming previous studies, we found that additional, unknown chromosomally mediated resistance mechanisms remain to be determined. In our study, 11 out of 12 strains and 3 out of 10 strains from CF patients and non-CF patients, respectively, were hypermutable. This extremely high proportion of mutator strains should be taken into consideration for the treatment of multiresistant P. aeruginosa.

A Critical Evaluation of Newer β-Lactam Antibiotics for Treatment of Pseudomonas aeruginosa Infections

2020 ◽  
pp. 106002802097400
Author(s):  
Kathleen C. Blomquist ◽  
David E. Nix
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Data ◽  
Therapeutic Potential ◽  
Data Extraction ◽  
Relevant Literature ◽  
Acquired Resistance ◽  
Critical Evaluation ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Study Selection

Objective: This article critically evaluates common Pseudomonas aeruginosa resistance mechanisms and the properties newer β-lactam antimicrobials possess to evade these mechanisms. Data Sources: An extensive PubMed, Google Scholar, and ClinicalTrials.gov search was conducted (January 1995 to July 2020) to identify relevant literature on epidemiology, resistance mechanisms, antipseudomonal agents, newer β-lactam agents, and clinical data available pertaining to P aeruginosa. Study Selection and Data Extraction: Relevant published articles and package inserts were reviewed for inclusion. Data Synthesis: Therapeutic options to treat P aeruginosa infections are limited because of its intrinsic and acquired resistance mechanisms. The goal was to identify advances with newer β-lactams and characterize improvements in therapeutic potential for P aeruginosa infections. Relevance to Patient Care and Clinical Practice: Multidrug-resistant (MDR) P aeruginosa isolates are increasingly encountered from a variety of infections. This review highlights potential activity gains of newer β-lactam antibacterial drugs and the current clinical data to support their use. Pharmacists will be asked to recommend or evaluate the use of these agents and need to be aware of information specific to P aeruginosa, which differs from experience derived from Enterobacterales infections. Conclusions: Newer agents, including ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, and cefiderocol, are useful for the treatment of MDR P aeruginosa infections. These agents offer improved efficacy and less toxicity compared with aminoglycosides and polymyxins and can be used for pathogens that are resistant to first-line antipseudomonal β-lactams. Selection of one agent over another should consider availability, turnaround of susceptibility testing, and product cost. Efficacy data specific for pseudomonal infections are limited, and there are no direct comparisons between the newer agents.

scholarly journals Molecular findings reveal possible resistance mechanisms in a patient with ALK-rearranged lung cancer: a case report and literature review

ESMO Open ◽  
2019 ◽  
Vol 4 (5) ◽  
pp. e000561 ◽  
Author(s):  
Anastasia Kougioumtzi ◽  
Panagiotis Ntellas ◽  
Eirini Papadopoulou ◽  
George Nasioulas ◽  
Eleftherios Kampletsas ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Disease Progression ◽  
Kinase Inhibitors ◽  
Wide Spectrum ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Molecular Testing ◽  
Liquid Biopsies ◽  
Disease Biology ◽  
Remarkable Progress

Background: Non-small-cell lung cancer (NSCLC) is recognised as a particularly heterogeneous disease, encompassing a wide spectrum of distinct molecular subtypes. With increased understanding of disease biology and mechanisms of progression, treatment of NSCLC has made remarkable progress in the past two decades. Molecular testing is considered the hallmark for the diagnosis and treatment of NSCLC, with liquid biopsies being more and more often applied in the clinical setting during the recent years. Rearrangement of the ALK gene which results in the generation of fusion oncogenes is a common molecular event in NSCLCs. Among ALK fusion transcripts, EML4-ALK fusion is frequently observed and can be targeted with ALK tyrosine kinase inhibitors (TKI). However, acquired resistance and disease progression in many cases are inevitable.Method: Here, we present the case of a patient with NSCLC treated with TKIs, in which molecular profiling of the tumour was performed with different methods of tissue and plasma testing at each disease progression. A review of the literature was further conducted to offer insights into the resistance mechanisms of ALK-rearranged NSCLC.Conclusions: Based on the results, the EML4-ALK fusion initially detected in tumour tissue was preserved throughout the course of the disease. Two additional ALK mutations were later detected in the tissue and plasma and are likely to have caused resistance to the administered TKIs. Continued research into the mechanisms of acquired resistance is required in order to increase the benefit of the patients treated with targeted ALK TKIs.

scholarly journals Evaluation of different phenotypic tests for detection of metallo-β-lactamases in imipenem-resistant Pseudomonas aeruginosa

2017 ◽  
Vol 9 (04) ◽  
pp. 249-253 ◽  
Author(s):  
Rohit Sachdeva ◽  
Babita Sharma ◽  
Rajni Sharma
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Large Scale ◽  
Wide Spectrum ◽  
Carbapenem Resistance ◽  
Resistance Mechanisms ◽  
Clinical Samples ◽  
Resistant Strains ◽  
Synergy Test ◽  
Phenotypic Tests ◽  
Simple Screening

Abstract PURPOSE: Pseudomonas aeruginosa causes a wide spectrum of infections including bacteremia, pneumonia, urinary tract infection, etc., Metallo-beta-lactamase (MBL) producing P. aeruginosa is an emerging threat and cause of concern as they have emerged as one of the most feared resistance mechanisms. This study was designed to know the prevalence of MBL production in P. aeruginosa and to evaluate the four phenotypic tests for detection of MBL production in imipenem-resistant clinical isolates of P. aeruginosa. METHODS: Totally, 800 isolates of P. aeruginosa isolated from various clinical samples were evaluated for carbapenem resistance and MBL production. All imipenem-resistant strains were tested for carabapenemase production by modified Hodge test. Screening for MBL production was done by double-disc synergy test and combined disc test (CDT). Confirmation of MBL production was done by the E-test (Ab BioDisk, Solna, Sweden). RESULTS: Out of the 800 isolates of P. aeruginosa, 250 isolates were found resistant to imipenem. Based on the results of E-test, 147 (18.37%) isolates of P. aeruginosa were positive for MBL production. The CDT has the highest sensitivity and specificity for the detection of MBL production as compared to other tests. CONCLUSION: The results of this study are indicative that MBL production is an important mechanism of carbapenem resistance among P. aeruginosa. Use of simple screening test like CDT will be crucial step toward large-scale monitoring of these emerging resistant determinants. Phenotypic test for MBL production has to be standardized, and all the isolates should be routinely screened for MBL production.

Stress responses as determinants of antimicrobial resistance in Pseudomonas aeruginosa: multidrug efflux and more

2014 ◽  
Vol 60 (12) ◽  
pp. 783-791 ◽  
Author(s):  
Keith Poole
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Resistance ◽  
Environmental Stress ◽  
Stress Responses ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Resistant Organism ◽  
Multidrug Efflux ◽  
Resistance Development ◽  
Endogenous Genes

Pseudomonas aeruginosa is a notoriously antimicrobial-resistant organism that is increasingly refractory to antimicrobial chemotherapy. While the usual array of acquired resistance mechanisms contribute to resistance development in this organism a multitude of endogenous genes also play a role. These include a variety of multidrug efflux loci that contribute to both intrinsic and acquired antimicrobial resistance. Despite their roles in resistance, however, it is clear that these efflux systems function in more than just antimicrobial efflux. Indeed, recent data indicate that they are recruited in response to environmental stress and, therefore, function as components of the organism’s stress responses. In fact, a number of endogenous resistance-promoting genes are linked to environmental stress, functioning as part of known stress responses or recruited in response to a variety of environmental stress stimuli. Stress responses are, thus, important determinants of antimicrobial resistance in P. aeruginosa. As such, they represent possible therapeutic targets in countering antimicrobial resistance in this organism.

scholarly journals Inference of the phenotypic resistance profile of Pseudomonas aeruginosa through an interpretative reading of the antibiogram in a pediatric hospital. 2006-2014.

2016 ◽  
Vol 64 (3) ◽  
pp. 409
Author(s):  
Juan Jailer Arango ◽  
Aura Lucia Leal ◽  
Maria Del Pilar Montilla ◽  
German Camacho Moreno
Keyword(s):  
Pseudomonas Aeruginosa ◽  
High Capacity ◽  
Pediatric Intensive Care ◽  
Opportunistic Pathogen ◽  
Resistance Mechanisms ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Resistance Phenotype ◽  
Phenotypic Resistance ◽  
Male Subjects

Introduction: Pseudomonas aeruginosa behaves as an opportunistic pathogen involved in hospital infections, with high capacity to generate resistance to antibiotic treatment. The interpretative reading of the antibiogram makes possible inferring these resistance mechanisms and establishing appropriate antibiotic treatment.Objective: The interpretative reading of the antibiogram seeks to infer the resistance phenotype of P. aeruginosa at Fundación Hospital de la Misericordia (HOMI, by its acronym in Spanish) between 2006 and 2014.Materials and methods: Descriptive cross-sectional study where a search of positive antibiogram reports for P. aeruginosa was performed. The resistance phenotype was deduced based on the interpretative reading of the antibiogram.Results: A sample of 463 positive antibiograms for P. aeruginosa was obtained; these samples were taken from children aged 0 to 17, showing a higher prevalence among infants and toddlers. The antibiograms mainly came from male subjects (62.2%). The most frequent hospitalization services were: PICU —pediatric intensive care unit— (30.2%) and general hospitalization (27.3%). The most common sources of isolation were: blood (24.4%) and urine (23.8%). 11 phenotypes were characterized, being the most common: natural phenotype (63.2%), loss of porin OprD (5.7%) and partial and full AmpC derepression (8.4% and 8.2%, respectively).Conclusion: Isolation of P. aeruginosa at HOMI predominantly shows a natural phenotype. The interpretative reading of the antibiogram allowed inferring 11 phenotypes.

scholarly journals Phenotypic and molecular characterization of antimicrobial resistance and virulence factors in Pseudomonas aeruginosa clinical isolates from Recife, State of Pernambuco, Brazil

2012 ◽  
Vol 45 (6) ◽  
pp. 707-712 ◽  
Author(s):  
Paula Regina Luna de Araújo Jácome ◽  
Lílian Rodrigues Alves ◽  
Adriane Borges Cabral ◽  
Ana Catarina Souza Lopes ◽  
Maria Amélia Vieira Maciel
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Resistance ◽  
Virulence Factors ◽  
Wide Spectrum ◽  
Carbapenem Resistance ◽  
Resistance Mechanisms ◽  
Public Hospitals ◽  
Control Measures ◽  
Infection Control Measures ◽  
Reducing Costs

INTRODUCTION: The emergence of carbapenem resistance mechanisms in Pseudomonas aeruginosa has been outstanding due to the wide spectrum of antimicrobial degradation of these bacteria, reducing of therapeutic options. METHODS: Sixty-one clinical strains of P. aeruginosa isolated from five public hospitals in Recife, Pernambuco, Brazil, were examined between 2006 and 2010, aiming of evaluating the profiles of virulence, resistance to antimicrobials, presence of metallo-β-lactamase (MBL) genes, and clonal relationship among isolates. RESULTS: A high percentage of virulence factors (34.4% mucoid colonies; 70.5% pyocyanin; 93.4% gelatinase positives; and 72.1% hemolysin positive) and a high percentage of antimicrobial resistance rates (4.9% pan-resistant and 54.1% multi-drug resistant isolates) were observed. Among the 29 isolates resistant to imipenem and/or ceftazidime, 44.8% (13/29) were MBL producers by phenotypic evaluation, and of these, 46.2% (6/13) were positive for the blaSPM-1 gene. The blaIMP and blaVIM genes were not detected. The molecular typing revealed 21 molecular profiles of which seven were detected in distinct hospitals and periods. Among the six positive blaSPM-1 isolates, three presented the same clonal profile and were from the same hospital, whereas the other three presented different clonal profiles. CONCLUSIONS: These results revealed that P. aeruginosa is able to accumulate different resistance and virulence factors, making the treatment of infections difficult. The identification of blaSPM-1 genes and the dissemination of clones in different hospitals, indicate the need for stricter application of infection control measures in hospitals in Recife, Brazil, aiming at reducing costs and damages caused by P. aeruginosa infections.

scholarly journals Characterization of a Carbapenem-Hydrolyzing Enzyme, PoxB, in Pseudomonas aeruginosa PAO1

2015 ◽  
Vol 60 (2) ◽  
pp. 936-945 ◽  
Author(s):  
Diansy Zincke ◽  
Deepak Balasubramanian ◽  
Lynn L. Silver ◽  
Kalai Mathee
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Enzyme Inhibitors ◽  
Acquired Resistance ◽  
Opportunistic Pathogen ◽  
Inducible Promoter ◽  
Upstream Open Reading Frame ◽  
Antimicrobial Drugs ◽  
Content Type ◽  
Class D

ABSTRACTPseudomonas aeruginosais an opportunistic pathogen often associated with severe and life-threatening infections that are highly impervious to treatment. This microbe readily exhibits intrinsic and acquired resistance to varied antimicrobial drugs. Resistance to penicillin-like compounds is commonplace and provided by the chromosomal AmpC β-lactamase. A second, chromosomally encoded β-lactamase, PoxB, has previously been reported inP. aeruginosa. In the present work, the contribution of this class D enzyme was investigated using a series of clean in-frameampC,poxB, andoprDdeletions, as well as complementation by expression under the control of an inducible promoter. WhilepoxBdeletions failed to alter β-lactam sensitivities, expression ofpoxBinampC-deficient backgrounds decreased susceptibility to both meropenem and doripenem but had no effect on imipenem, penicillin, and cephalosporin MICs. However, when expressed in anampCpoxB-deficient background, that additionally lacked the outer membrane porin-encoding geneoprD, PoxB significantly increased the imipenem as well as the meropenem and doripenem MICs. Like other class D carbapenem-hydrolyzing β-lactamases, PoxB was only poorly inhibited by class A enzyme inhibitors, but a novel non-β-lactam compound, avibactam, was a slightly better inhibitor of PoxB activity.In vitrosusceptibility testing with a clinical concentration of avibactam, however, failed to reduce PoxB activity against the carbapenems. In addition,poxBwas found to be cotranscribed with an upstream open reading frame,poxA, which itself was shown to encode a 32-kDa protein of yet unknown function.

scholarly journals The Prevalence of Metallo-β-Lactamases and Efflux-Mediated Mechanisms in Carbapenem Nonsusceptible Nosocomial Pseudomonas aeruginosa Isolated in Moscow in 2012–2015

2015 ◽  
Vol 70 (6) ◽  
pp. 679-683
Author(s):  
Anna Valer'evna Lazareva ◽  
Ol'ga Andreevna Kryzhanovskaya ◽  
Yuliya Aleksandrovna Bocharova ◽  
Igor' Viktorovich Chebotar' ◽  
Nikolay Andreevich Mayanskiy
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Carbapenem Resistance ◽  
Opportunistic Pathogen ◽  
Resistance Mechanisms ◽  
Active Efflux ◽  
Minimal Inhibitory Concentrations ◽  
Highly Active ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Carbonyl Cyanide

Background. Pseudomonas aeruginosa, the major nosocomial opportunistic pathogen, is an important cause of infectious morbidity and mortality among immunocompromised patients.Objective. To establish the role of metallo-β-lactamases (MBL) and efflux-mediated mechanisms in conferring carbapenem resistance in nosocomial isolates of P. aeruginosa.Methods. We analyzed carbapenem nonsusceptible nosocomial P. aeruginosa isolates obtained from pediatric and adult patients at three hospitals in Moscow in 2012–2015. Carbapenem susceptibility was assessed using the E-test. In addition, minimal inhibitory concentrations (MICs) of meropenem were tested by the broth microdilution method. The presence of MBL was determined using the EDTA-mediated suppression test. Efflux-dependent resistance was measured using an assay based on MIC modification by an ionophore carbonyl cyanide 3-chlorophenyl hydrazine (CCCP).Results. A total of 54 carbapenem nonsusceptible P. aeruginosa isolates was examined. The presence of an MBL was detected in 37 (69%) isolates, 29 (54%) isolates had efflux-mediated resistance. In 10 (19%) isolates neither MBL nor efflux activity was found. Five out of 6 isolates (83%) with highly active efflux were MBL-positive. Among isolates with low efflux activity, 74% (17/23) possessed MBL, whereas in isolates with no efflux the rate of MBL-positivity was 60% (15/25).Conclusion. The prevalence of MBL- and efflux-mediated carbapenem resistance in nosocomial P. aeruginosa is high. Moreover, our results reveal that several resistance mechanisms may combine at the isolate level. These data may contribute to the development of novel strategies in combating carbapenem resistance.

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