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.

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 Post-antibiotic era in hemodialysis? Two case reports of simultaneous colonization and bacteremia by multidrug-resistant bacteria

2020 ◽  
Author(s):  
Johanna M. Vanegas ◽  
Lorena Salazar-Ospina ◽  
Gustavo A. Roncancio ◽  
Julián Builes ◽  
Judy Natalia Jiménez
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Bacterial Infections ◽  
Case Reports ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Control Measures ◽  
Resistant Bacteria ◽  
Multidrug Resistant Bacteria ◽  
E Coli ◽  
Carbapenem Resistant

ABSTRACT The emergence of resistance mechanisms not only limits the therapeutic options for common bacterial infections but also worsens the prognosis in patients who have conditions that increase the risk of bacterial infections. Thus, the effectiveness of important medical advances that seek to improve the quality of life of patients with chronic diseases is threatened. We report the simultaneous colonization and bacteremia by multidrug-resistant bacteria in two hemodialysis patients. The first patient was colonized by carbapenem- and colistin-resistant Klebsiella pneumoniae, carbapenem-resistant Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA). The patient had a bacteremia by MRSA, and molecular typing methods confirmed the colonizing isolate was the same strain that caused infection. The second case is of a patient colonized by extended-spectrum beta-lactamases (ESBL)-producing Escherichia coli and carbapenem-resistant Pseudomonas aeruginosa. During the follow-up period, the patient presented three episodes of bacteremia, one of these caused by ESBL-producing E. coli. Molecular methods confirmed colonization by the same clone of ESBL-producing E. coli at two time points, but with a different genetic pattern to the strain isolated from the blood culture. Colonization by multidrug-resistant bacteria allows not only the spread of these microorganisms, but also increases the subsequent risk of infections with limited treatments options. In addition to infection control measures, it is important to establish policies for the prudent use of antibiotics in dialysis units.

scholarly journals Review of Ceftazidime-Avibactam for the Treatment of Infections Caused by Pseudomonas aeruginosa

Antibiotics ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1126
Author(s):  
George L. Daikos ◽  
Clóvis Arns da da Cunha ◽  
Gian Maria Rossolini ◽  
Gregory G. Stone ◽  
Nathalie Baillon-Plot ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Real World Data ◽  
Serious Infections ◽  
Tract Infections ◽  
Abdominal Infections ◽  
Hospital Acquired

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that causes a range of serious infections that are often challenging to treat, as this pathogen can express multiple resistance mechanisms, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) phenotypes. Ceftazidime–avibactam is a combination antimicrobial agent comprising ceftazidime, a third-generation semisynthetic cephalosporin, and avibactam, a novel non-β-lactam β-lactamase inhibitor. This review explores the potential role of ceftazidime–avibactam for the treatment of P. aeruginosa infections. Ceftazidime–avibactam has good in vitro activity against P. aeruginosa relative to comparator β-lactam agents and fluoroquinolones, comparable to amikacin and ceftolozane–tazobactam. In Phase 3 clinical trials, ceftazidime–avibactam has generally demonstrated similar clinical and microbiological outcomes to comparators in patients with complicated intra-abdominal infections, complicated urinary tract infections or hospital-acquired/ventilator-associated pneumonia caused by P. aeruginosa. Although real-world data are limited, favourable outcomes with ceftazidime–avibactam treatment have been reported in some patients with MDR and XDR P. aeruginosa infections. Thus, ceftazidime–avibactam may have a potentially important role in the management of serious and complicated P. aeruginosa infections, including those caused by MDR and XDR strains.

scholarly journals Prevalence, Risk Factors, and Molecular Epidemiology of Intestinal Carbapenem-Resistant Pseudomonas aeruginosa

2021 ◽  
Author(s):  
Yanyan Hu ◽  
Yan Qing ◽  
Jiawei Chen ◽  
Congcong Liu ◽  
Jiayue Lu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Pseudomonas Aeruginosa ◽  
Gastrointestinal Tract ◽  
Resistance Genes ◽  
Acquired Resistance ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Human Gastrointestinal Tract ◽  
Content Type ◽  
Carbapenem Resistant

Pseudomonas aeruginosa may become multidrug-resistant (MDR) due to multiple inherited and acquired resistance mechanisms. The human gastrointestinal tract is known as a reservoir of P. aeruginosa and its resistance genes.

scholarly journals Performance of Four Fosfomycin Susceptibility Testing Methods against an International Collection of Clinical Pseudomonas aeruginosa Isolates

2020 ◽  
Vol 58 (10) ◽  
Author(s):  
Elizabeth C. Smith ◽  
Hunter V. Brigman ◽  
Jadyn C. Anderson ◽  
Christopher L. Emery ◽  
Tiffany E. Bias ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Susceptibility Testing ◽  
Wide Spectrum ◽  
Multidrug Resistant ◽  
Supporting Evidence ◽  
Broth Microdilution ◽  
Testing Methods ◽  
Content Type ◽  
E Coli ◽  
Agar Dilution

ABSTRACT Fosfomycin has been shown to have a wide spectrum of activity against multidrug-resistant Gram-negative bacteria; however, breakpoints have been established only for Escherichia coli or Enterobacterales per the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST), respectively. A lack of additional organism breakpoints limits clinical use of this agent and has prompted extrapolation of these interpretive categories to other organisms like Pseudomonas aeruginosa without supporting evidence. Further complicating the utility of fosfomycin is the specified method for MIC determination, namely, agar dilution, which is not widely available and is both labor and time intensive. We therefore sought to determine the susceptibility of a large international collection of P. aeruginosa isolates (n = 198) to fosfomycin and to compare testing agreement rates across four methods: agar dilution, broth microdilution, disk diffusion, and Etest. Results were interpreted according to CLSI E. coli breakpoints, with 49.0 to 85.8% considered susceptible, dependent upon the testing method used. Epidemiological cutoff values were calculated and determined to be 256 μg/ml and 512 μg/ml for agar dilution and broth microdilution, respectively. Agreement rates were analyzed using both agar dilution and broth microdilution with a resulting high essential agreement rate of 91.3% between the two susceptibility testing methods. These results indicate that broth microdilution may be a reliable method for fosfomycin susceptibility testing against P. aeruginosa and stress the need for P. aeruginosa-specific breakpoints.

scholarly journals Plasmid-Mediated OqxAB Is an Important Mechanism for Nitrofurantoin Resistance in Escherichia coli

2015 ◽  
Vol 60 (1) ◽  
pp. 537-543 ◽  
Author(s):  
Pak-Leung Ho ◽  
Ka-Ying Ng ◽  
Wai-U Lo ◽  
Pierra Y. Law ◽  
Eileen Ling-Yi Lai ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Efflux Pump ◽  
Geometric Mean ◽  
Resistance Mechanism ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Content Type ◽  
E Coli ◽  
High Level ◽  
Tract Infections

ABSTRACTIncreasing consumption of nitrofurantoin (NIT) for treatment of acute uncomplicated urinary tract infections (UTI) highlights the need to monitor emerging NIT resistance mechanisms. This study investigated the molecular epidemiology of the multidrug-resistant efflux geneoqxABand its contribution to nitrofurantoin resistance by usingEscherichia coliisolates originating from patients with UTI (n= 205; collected in 2004 to 2013) and food-producing animals (n= 136; collected in 2012 to 2013) in Hong Kong. TheoqxABgene was highly prevalent among NIT-intermediate (11.5% to 45.5%) and -resistant (39.2% to 65.5%) isolates but rare (0% to 1.7%) among NIT-susceptible (NIT-S) isolates. In our isolates, theoqxABgene was associated with IS26and was carried by plasmids of diverse replicon types. Multilocus sequence typing revealed that the clones ofoqxAB-positiveE. coliwere diverse. The combination ofoqxABandnfsAmutations was found to be sufficient for high-level NIT resistance. Curing ofoqxAB-carrying plasmids from 20 NIT-intermediate/resistant UTI isolates markedly reduced the geometric mean MIC of NIT from 168.9 μg/ml to 34.3 μg/ml. In the plasmid-cured variants, 20% (1/5) of isolates withnfsAmutations were NIT-S, while 80% (12/15) of isolates withoutnfsAmutations were NIT-S (P= 0.015). The presence of plasmid-basedoqxABincreased the mutation prevention concentration of NIT from 128 μg/ml to 256 μg/ml and facilitated the development of clinically important levels of nitrofurantoin resistance. In conclusion, plasmid-mediatedoqxABis an important nitrofurantoin resistance mechanism. There is a great need to monitor the dissemination of this transferable multidrug-resistant efflux pump.

scholarly journals It’s Not Easy Being Green: A Narrative Review on the Microbiology, Virulence and Therapeutic Prospects of Multidrug-Resistant Pseudomonas aeruginosa

Antibiotics ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 42
Author(s):  
Payam Behzadi ◽  
Zoltán Baráth ◽  
Márió Gajdács
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Excess Mortality ◽  
Review Paper ◽  
Acquired Resistance ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Gram Negative Bacteria ◽  
Pathogenic Role ◽  
Carbapenem Resistant ◽  
Resistant Strains

Pseudomonas aeruginosa is the most frequent cause of infection among non-fermenting Gram-negative bacteria, predominantly affecting immunocompromised patients, but its pathogenic role should not be disregarded in immunocompetent patients. These pathogens present a concerning therapeutic challenge to clinicians, both in community and in hospital settings, due to their increasing prevalence of resistance, and this may lead to prolonged therapy, sequelae, and excess mortality in the affected patient population. The resistance mechanisms of P. aeruginosa may be classified into intrinsic and acquired resistance mechanisms. These mechanisms lead to occurrence of resistant strains against important antibiotics—relevant in the treatment of P. aeruginosa infections—such as β-lactams, quinolones, aminoglycosides, and colistin. The occurrence of a specific resistotype of P. aeruginosa, namely the emergence of carbapenem-resistant but cephalosporin-susceptible (Car-R/Ceph-S) strains, has received substantial attention from clinical microbiologists and infection control specialists; nevertheless, the available literature on this topic is still scarce. The aim of this present review paper is to provide a concise summary on the adaptability, virulence, and antibiotic resistance of P. aeruginosa to a readership of basic scientists and clinicians.

scholarly journals Prevalence and Characterization of ESBL/AmpC Producing Escherichia coli from Fresh Meat in Portugal

Antibiotics ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1333
Author(s):  
Lurdes Clemente ◽  
Célia Leão ◽  
Laura Moura ◽  
Teresa Albuquerque ◽  
Ana Amaro
Keyword(s):  
Escherichia Coli ◽  
Acquired Resistance ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Selective Medium ◽  
Poultry Meat ◽  
Broiler Meat ◽  
E Coli ◽  
Antimicrobial Resistance Genes ◽  
Meat Samples

The present study aimed to characterize the extended-spectrum β-lactamases and plasmid-mediated AmpC β-lactamases (ESBL/PMAβ) among Escherichia coli producers isolated from beef, pork, and poultry meat collected at retail, in Portugal. A total of 638 meat samples were collected and inoculated on selective medium for the search of E. coli resistant to 3rd generation cephalosporins. Isolates were characterized by antimicrobial susceptibility testing, molecular assays targeting ESBL/AmpC, plasmid-mediated quinolone resistance (PMQR), and plasmid-mediated colistin resistance (PMCR) encoding genes. The highest frequency of E. coli non-wild type to 3rd generation cephalosporins and fluoroquinolones was observed in broiler meat (30.3% and 93.3%, respectively). Overall, a diversity of acquired resistance mechanisms, were detected: blaESBL [blaCTX-M-1 (n = 19), blaCTX-M-15 (n = 4), blaCTX-M-32 (n = 12), blaCTX-M-55 (n = 8), blaCTX-M-65 (n = 4), blaCTX-M-27 (n = 2), blaCTX-M-9 (n = 1), blaCTX-M-14 (n = 11), blaSHV-12 (n = 27), blaTEM-52 (n = 1)], blaPMAβ [blaCMY-2 (n = 8)], PMQR [qnrB (n = 27), qnrS (n = 21) and aac(6’)-Ib-type (n = 4)] and PMCR [mcr-1 (n = 8)]. Our study highlights that consumers may be exposed through the food chain to multidrug-resistant E. coli carrying diverse plasmid-mediated antimicrobial resistance genes, posing a great hazard to food safety and a public health risk.

scholarly journals Draft Genome Sequences of Two Pseudomonas aeruginosa Multidrug-Resistant Clinical Isolates, PAL0.1 and PAL1.1

2018 ◽  
Vol 7 (17) ◽  
Author(s):  
Teddy Grandjean ◽  
Rémi Le Guern ◽  
Claire Duployez ◽  
Karine Faure ◽  
Eric Kipnis ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Draft Genome ◽  
Acquired Resistance ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Blood Cultures ◽  
Ventilator Associated Pneumonia ◽  
Genome Sequences ◽  
Content Type ◽  
Resistant Strains

Pseudomonas aeruginosa infections are challenging due to intrinsic and acquired resistance mechanisms. We report here the draft genome sequences of two multidrug-resistant strains—PAL0.1, isolated from the airways of an intensive care unit (ICU) patient with ventilator-associated pneumonia, and PAL1.1, isolated from blood cultures of an ICU patient with sepsis.

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.

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