scholarly journals Impact of MIC Range for Pseudomonas aeruginosa and Streptococcus pneumoniae on the CeftolozaneIn VivoPharmacokinetic/Pharmacodynamic Target

2014 ◽  
Vol 58 (10) ◽  
pp. 6311-6314 ◽  
Author(s):  
A. J. Lepak ◽  
A. Reda ◽  
K. Marchillo ◽  
J. Van Hecker ◽  
W. A. Craig ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Streptococcus Pneumoniae ◽  
Resistance Mechanisms ◽  
Drug Resistant ◽  
Content Type ◽  
The Times

ABSTRACTCeftolozane is a novel cephalosporin with activity against drug-resistant pathogens, includingPseudomonas aeruginosaandStreptococcus pneumoniae. Thein vivoinvestigation reported here tested the limits of this drug against 20P. aeruginosaandS. pneumoniaeisolates across a wide MIC range and defined resistance mechanisms. The times above the MIC (T>MIC) targets for stasis and 1- and 2-log reductions were 31%, 39%, and 42% forP. aeruginosaand 18%, 24%, and 27% forS. pneumoniae, respectively. The 1-log endpoint was achieved for strains with MICs as high as 16 μg/ml.

scholarly journals Challenging Antimicrobial Susceptibility and Evolution of Resistance (OXA-681) during Treatment of a Long-Term Nosocomial Infection Caused by a Pseudomonas aeruginosa ST175 Clone

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Jorge Arca-Suárez ◽  
Pablo Fraile-Ribot ◽  
Juan Carlos Vázquez-Ucha ◽  
Gabriel Cabot ◽  
Marta Martínez-Guitián ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Nosocomial Infection ◽  
Resistance Mechanisms ◽  
Cross Resistance ◽  
The Novel ◽  
Content Type ◽  
Narrow Spectrum ◽  
Extended Spectrum

ABSTRACT Selection of extended-spectrum mutations in narrow-spectrum oxacillinases (e.g., OXA-2 and OXA-10) is an emerging mechanism for development of in vivo resistance to ceftolozane-tazobactam and ceftazidime-avibactam in Pseudomonas aeruginosa. Detection of these challenging enzymes therefore seems essential to prevent clinical failure, but the complex phenotypic plasticity exhibited by this species may often lead to their underestimation. The underlying resistance mechanisms of two sequence type 175 (ST175) P. aeruginosa isolates showing multidrug-resistant phenotypes and recovered at early and late stages of a long-term nosocomial infection were evaluated. Whole-genome sequencing (WGS) was used to investigate resistance genomics, whereas molecular and biochemical methods were used for characterization of a novel extended-spectrum OXA-2 variant selected during therapy. The metallo-β-lactamase blaVIM-20 and the narrow-spectrum oxacillinase blaOXA-2 were present in both isolates, although they differed by an inactivating mutation in the mexB subunit, present only in the early isolate, and in a mutation in the blaOXA-2 β-lactamase, present only in the final isolate. The new OXA-2 variant, designated OXA-681, conferred elevated MICs of the novel cephalosporin–β-lactamase inhibitor combinations in a PAO1 background. Compared to OXA-2, kinetic parameters of the OXA-681 enzyme revealed a substantial increase in the hydrolysis of cephalosporins, including ceftolozane. We describe the emergence of the novel variant OXA-681 during treatment of a nosocomial infection caused by a Pseudomonas aeruginosa ST175 high-risk clone. The ability of OXA-681 to confer cross-resistance to ceftolozane-tazobactam and ceftazidime-avibactam together with the complex antimicrobial resistance profiles exhibited by the clinical strains harboring this new enzyme argue for maintaining active surveillance on emerging broad-spectrum resistance in P. aeruginosa.

scholarly journals In vivo emergence of resistance to cefiderocol in an XDR Pseudomonas aeruginosa and an MDR Citrobacter koseri after prolonged therapy: a case report.

2020 ◽  
Author(s):  
Carolina Grande Perez ◽  
Evelyne Maillart ◽  
Véronique Yvette Miendje Deyi ◽  
Te Din Daniel Huang ◽  
Prochore Kamgang ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Class A ◽  
Stewardship Program ◽  
Class D ◽  
Emergence Of Resistance

Abstract The non-fermenters, e.g. Pseudomonas aeruginosa, and the extended spectrum β-lactamases or carbapenemases producing enterobacteriaceae represent a serious threat for patients admitted in Intensive Care Units (ICUs). News antibiotics have been developed to treat multidrug resistant bacteria. However, treatment emerging resistance has been shown for many of these newest antibiotics. Cefiderocol, a siderophore-antibiotic, has been developed to overcome most of the resistance mechanisms and shows great efficacy against most multi-drug resistant and extensively drug resistant Gram-negative bacteria, including the non-fermenters. We report the case of a patient abundantly treated with antibiotics. He received 158 days of antibiotherapy on 230 hospitalization days, including a six-week course of cefiderocol, in 14 different treatment lines. The patient developed a Pseudomonas aeruginosa (MIC: 8 µg/ml, GES type ESBL) and a Citrobacter koseri (MIC: 16 µg/ml, CTX-M group 9 type class A β-lactamase and a class D OXA-1 oxacillinase) resistant to cefiderocol. This antibiotic should be used with caution to preserve its efficacy, within a strict antimicrobial stewardship program.

scholarly journals Two Novel Bacteriophages Improve Survival in Galleria mellonella Infection and Mouse Acute Pneumonia Models Infected with Extensively Drug-Resistant Pseudomonas aeruginosa

2019 ◽  
Vol 85 (9) ◽  
Author(s):  
Jongsoo Jeon ◽  
Dongeun Yong
Keyword(s):  
Pseudomonas Aeruginosa ◽  
In Silico ◽  
Galleria Mellonella ◽  
Drug Resistant ◽  
Content Type ◽  
Bacteriolytic Activity ◽  
Extensively Drug Resistant ◽  
Acute Pneumonia

ABSTRACT Extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) is a life-threatening pathogen that causes serious global problems. Here, we investigated two novel P. aeruginosa bacteriophages (phages), Bϕ-R656 and Bϕ-R1836, in vitro, in silico, and in vivo to evaluate the potential of phage therapy to control XDR-PA clinical strains. Bϕ-R656 and Bϕ-R1836 belong to the Siphoviridae family and exhibited broad host ranges which could lyse 18 (64%) and 14 (50%) of the 28 XDR-PA strains. In addition, the two phages showed strong bacteriolytic activity against XDR-PA host strains from pneumonia patients. The whole genomes of Bϕ-R656 and Bϕ-R1836 have linear double-stranded DNA of 60,919 and 37,714 bp, respectively. The complete sequence of Bϕ-R656 had very low similarity to the previously discovered P. aeruginosa phages in GenBank, but phage Bϕ-R1836 exhibited 98% and 91% nucleotide similarity to Pseudomonas phages YMC12/01/R24 and PA1/KOR/2010, respectively. In the two in vivo infection models, treatment with Bϕ-R656 and Bϕ-R1836 enhanced the survival of Galleria mellonella larvae (50% and 60%, respectively) at 72 h postinfection and pneumonia-model mice (66% and 83%, respectively) at 12 days postinfection compared with untreated controls. Treatment with Bϕ-R656 or Bϕ-R1836 also significantly decreased the bacterial load in the lungs of the mouse pneumonia model (>6 log10 CFU and >4 log10 CFU, respectively) on day 5. IMPORTANCE In this study, two novel P. aeruginosa phages, Bϕ-R656 and Bϕ-R1836, were evaluated in vitro, in silico, and in vivo for therapeutic efficacy and safety as an alternative antibacterial agent to control XDR-PA strains collected from pneumonia patients. Both phages exhibited potent bacteriolytic activity and greatly improved survival in G. mellonella larva infection and a mouse acute pneumonia model. Based on these results, we strongly predict that these two new phages could be used as fast-acting and safe alternative biological weapons against XDR-PA infections.

scholarly journals Draft Genome Sequence of the Extensively Drug-Resistant Pseudomonas aeruginosa Clinical Isolate TUEPA7472

2018 ◽  
Vol 7 (12) ◽  
Author(s):  
Henrike Miess ◽  
Ghazaleh Jahanshah ◽  
Heike Brötz-Oesterhelt ◽  
Matthias Willmann ◽  
Silke Peter ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Genome Sequence ◽  
Draft Genome ◽  
Resistance Mechanisms ◽  
Draft Genome Sequence ◽  
Drug Resistant ◽  
Gram Negative ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Insight Into

Pseudomonas aeruginosa TUEPA7472 is extensively drug resistant (XDR) and is a representative Gram-negative rod that is multiresistant toward 4 classes of clinically relevant antibiotics (4MRGN). The 6.8-Mb draft genome sequence of this strain provides insight into these resistance mechanisms and the potential of the strain to produce virulence factors.

scholarly journals Multicenter Evaluation of Ceftazidime-Avibactam and Ceftolozane-Tazobactam Inhibitory Activity against Meropenem-Nonsusceptible Pseudomonas aeruginosa from Blood, Respiratory Tract, and Wounds

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Mordechai Grupper ◽  
Christina Sutherland ◽  
David P. Nicolau
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inhibitory Activity ◽  
Clinical Utility ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Broth Microdilution ◽  
Content Type ◽  
Carbapenem Resistant

ABSTRACT The recent escalation of occurrences of carbapenem-resistant Pseudomonas aeruginosa has been recognized globally and threatens to erode the widespread clinical utility of the carbapenem class of compounds for this prevalent health care-associated pathogen. Here, we compared the in vitro inhibitory activity of ceftazidime-avibactam and ceftolozane-tazobactam against 290 meropenem-nonsusceptible Pseudomonas aeruginosa nonduplicate clinical isolates from 34 U.S. hospitals using reference broth microdilution methods. Ceftazidime-avibactam and ceftolozane-tazobactam were active, with ceftolozane-tazobactam having significantly higher inhibitory activity than ceftazidime-avibactam. The heightened inhibitory activity of ceftolozane-tazobactam was sustained when the site of origin (respiratory, blood, or wound) and nonsusceptibility to other β-lactam antimicrobials was considered. An extensive genotypic search for enzymatically driven β-lactam resistance mechanisms revealed the exclusive presence of the VIM metallo-β-lactamase among only 4% of the subset of isolates nonsusceptible to ceftazidime-avibactam, ceftolozane-tazobactam, or both. These findings suggest an important role for both ceftazidime-avibactam and ceftolozane-tazobactam against carbapenem-nonsusceptible Pseudomonas aeruginosa. Further in vitro and in vivo studies are needed to better define the clinical utility of these novel therapies against the increasingly prevalent threat of multidrug-resistant Pseudomonas aeruginosa.

scholarly journals Genomics and Susceptibility Profiles of Extensively Drug-Resistant Pseudomonas aeruginosa Isolates from Spain

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Ester del Barrio-Tofiño ◽  
Carla López-Causapé ◽  
Gabriel Cabot ◽  
Alba Rivera ◽  
Natividad Benito ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Illumina Miseq ◽  
Resistance Mechanisms ◽  
Drug Resistant ◽  
Sequencing Data ◽  
Aminoglycoside Resistance ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Susceptibility Profiles

ABSTRACT This study assessed the molecular epidemiology, resistance mechanisms, and susceptibility profiles of a collection of 150 extensively drug-resistant (XDR) Pseudomonas aeruginosa clinical isolates obtained from a 2015 Spanish multicenter study, with a particular focus on resistome analysis in relation to ceftolozane-tazobactam susceptibility. Broth microdilution MICs revealed that nearly all (>95%) of the isolates were nonsusceptible to piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, imipenem, meropenem, and ciprofloxacin. Most of them were also resistant to tobramycin (77%), whereas nonsusceptibility rates were lower for ceftolozane-tazobactam (31%), amikacin (7%), and colistin (2%). Pulsed-field gel electrophoresis–multilocus sequence typing (PFGE-MLST) analysis revealed that nearly all of the isolates belonged to previously described high-risk clones. Sequence type 175 (ST175) was detected in all 9 participating hospitals and accounted for 68% (n = 101) of the XDR isolates, distantly followed by ST244 (n = 16), ST253 (n = 12), ST235 (n = 8), and ST111 (n = 2), which were detected only in 1 to 2 hospitals. Through phenotypic and molecular methods, the presence of horizontally acquired carbapenemases was detected in 21% of the isolates, mostly VIM (17%) and GES enzymes (4%). At least two representative isolates from each clone and hospital (n = 44) were fully sequenced on an Illumina MiSeq. Classical mutational mechanisms, such as those leading to the overexpression of the β-lactamase AmpC or efflux pumps, OprD inactivation, and/or quinolone resistance-determining regions (QRDR) mutations, were confirmed in most isolates and correlated well with the resistance phenotypes in the absence of horizontally acquired determinants. Ceftolozane-tazobactam resistance was not detected in carbapenemase-negative isolates, in agreement with sequencing data showing the absence of ampC mutations. The unique set of mutations responsible for the XDR phenotype of ST175 clone documented 7 years earlier were found to be conserved, denoting the long-term persistence of this specific XDR lineage in Spanish hospitals. Finally, other potentially relevant mutations were evidenced, including those in penicillin-binding protein 3 (PBP3), which is involved in β-lactam (including ceftolozane-tazobactam) resistance, and FusA1, which is linked to aminoglycoside resistance.

scholarly journals Activity of Imipenem-Relebactam against a Large Collection of Pseudomonas aeruginosa Clinical Isolates and Isogenic β-Lactam-Resistant Mutants

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Pablo A. Fraile-Ribot ◽  
Laura Zamorano ◽  
Rocío Orellana ◽  
Ester del Barrio-Tofiño ◽  
Irina Sánchez-Diener ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Resistance Mechanisms ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Large Panel ◽  
Resistant Mutants ◽  
Isogenic Mutants ◽  
Susceptibility Rate

ABSTRACT Imipenem and imipenem-relebactam MICs were determined for 1,445 Pseudomonas aeruginosa clinical isolates and a large panel of isogenic mutants showing the most relevant mutation-driven β-lactam resistance mechanisms. Imipenem-relebactam showed the highest susceptibility rate (97.3%), followed by colistin and ceftolozane-tazobactam (both 94.6%). Imipenem-relebactam MICs remained ≤2 μg/ml in all 16 isogenic PAO1 mutants and in 8 pairs of extensively drug-resistant clinical strains that had developed resistance to ceftolozane-tazobactam and ceftazidime-avibactam due to mutations in OXA-10 or AmpC.

scholarly journals In VivoComparison of CXA-101 (FR264205) with and without Tazobactam versus Piperacillin-Tazobactam Using Human Simulated Exposures against Phenotypically Diverse Gram-Negative Organisms

2011 ◽  
Vol 56 (1) ◽  
pp. 544-549 ◽  
Author(s):  
Catharine C. Bulik ◽  
Pamela R. Tessier ◽  
Rebecca A. Keel ◽  
Christina A. Sutherland ◽  
David P. Nicolau
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Resistance Mechanisms ◽  
Infection Model ◽  
Gram Negative ◽  
Content Type ◽  
Comparison Groups ◽  
Gram Negative Organisms

ABSTRACTCXA-101 is a novel antipseudomonal cephalosporin with enhanced activity against Gram-negative organisms displaying various resistance mechanisms. This study evaluates the efficacy of exposures approximating human percent free time above the MIC (%fT > MIC) of CXA-101 with or without tazobactam and piperacillin-tazobactam (TZP) against target Gram-negative organisms, including those expressing extended-spectrum β-lactamases (ESBLs). Sixteen clinical Gram-negative isolates (6Pseudomonas aeruginosaisolates [piperacillin-tazobactam MIC range, 8 to 64 μg/ml], 4Escherichia coliisolates (2 ESBL and 2 non-ESBL expressing), and 4Klebsiella pneumoniaeisolates (3 ESBL and 1 non-ESBL expressing) were used in an immunocompetent murine thigh infection model. After infection, groups of mice were administered doses of CXA-101 with or without tazobactam (2:1) designed to approximate the %fT > MIC observed in humans given 1 g of CXA-101 with or without tazobactam every 8 h as a 1-h infusion. As a comparison, groups of mice were administered piperacillin-tazobactam doses designed to approximate the %fT > MIC observed in humans given 4.5 g piperacillin-tazobactam every 6 h as a 30-min infusion. Predicted piperacillin-tazobactam %fT > MIC exposures of greater than 40% resulted in static to >1 log decreases in CFU in non-ESBL-expressing organisms with MICs of ≤32 μg/ml after 24 h of therapy. Predicted CXA-101 with or without tazobactam %fT > MIC exposures of ≥37.5% resulted in 1- to 3-log-unit decreases in CFU in non-ESBL-expressing organisms, with MICs of ≤16 μg/ml after 24 h of therapy. With regard to the ESBL-expressing organisms, the inhibitor combinations showed enhanced CFU decreases versus CXA-101 alone. Due to enhancedin vitropotency and resultant increasedin vivoexposure, CXA-101 produced statistically significant reductions in CFU in 9 isolates compared with piperacillin-tazobactam. The addition of tazobactam to CXA-101 produced significant reductions in CFU for 7 isolates compared with piperacillin-tazobactam. Overall, human simulated exposures of CXA-101 with or without tazobactam demonstrated improved efficacy versus piperacillin-tazobactam.

scholarly journals Exogenous Alginate Protects Staphylococcus aureus from Killing by Pseudomonas aeruginosa

2019 ◽  
Vol 202 (8) ◽  
Author(s):  
Courtney E. Price ◽  
Dustin G. Brown ◽  
Dominique H. Limoli ◽  
Vanessa V. Phelan ◽  
George A. O’Toole
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Physical Space ◽  
Late Time ◽  
Protective Effects ◽  
Content Type ◽  
Alginate Production ◽  
The Impact

ABSTRACT Cystic fibrosis (CF) patients chronically infected with both Pseudomonas aeruginosa and Staphylococcus aureus have worse health outcomes than patients who are monoinfected with either P. aeruginosa or S. aureus. We showed previously that mucoid strains of P. aeruginosa can coexist with S. aureus in vitro due to the transcriptional downregulation of several toxic exoproducts typically produced by P. aeruginosa, including siderophores, rhamnolipids, and HQNO (2-heptyl-4-hydroxyquinoline N-oxide). Here, we demonstrate that exogenous alginate protects S. aureus from P. aeruginosa in both planktonic and biofilm coculture models under a variety of nutritional conditions. S. aureus protection in the presence of exogenous alginate is due to the transcriptional downregulation of pvdA, a gene required for the production of the iron-scavenging siderophore pyoverdine as well as the downregulation of the PQS (Pseudomonas quinolone signal) (2-heptyl-3,4-dihydroxyquinoline) quorum sensing system. The impact of exogenous alginate is independent of endogenous alginate production. We further demonstrate that coculture of mucoid P. aeruginosa with nonmucoid P. aeruginosa strains can mitigate the killing of S. aureus by the nonmucoid strain of P. aeruginosa, indicating that the mechanism that we describe here may function in vivo in the context of mixed infections. Finally, we investigated a panel of mucoid clinical isolates that retain the ability to kill S. aureus at late time points and show that each strain has a unique expression profile, indicating that mucoid isolates can overcome the S. aureus-protective effects of mucoidy in a strain-specific manner. IMPORTANCE CF patients are chronically infected by polymicrobial communities. The two dominant bacterial pathogens that infect the lungs of CF patients are P. aeruginosa and S. aureus, with ∼30% of patients coinfected by both species. Such coinfected individuals have worse outcomes than monoinfected patients, and both species persist within the same physical space. A variety of host and environmental factors have been demonstrated to promote P. aeruginosa-S. aureus coexistence, despite evidence that P. aeruginosa kills S. aureus when these organisms are cocultured in vitro. Thus, a better understanding of P. aeruginosa-S. aureus interactions, particularly mechanisms by which these microorganisms are able to coexist in proximal physical space, will lead to better-informed treatments for chronic polymicrobial infections.

scholarly journals Nosocomial Outbreak of Drug-Resistant Streptococcus pneumoniae Serotype 9V in an Adult Respiratory Medicine Ward

2016 ◽  
Vol 55 (3) ◽  
pp. 776-782 ◽  
Author(s):  
Elita Jauneikaite ◽  
Zareena Khan-Orakzai ◽  
Georgia Kapatai ◽  
Susannah Bloch ◽  
Julie Singleton ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Lower Respiratory Tract ◽  
Sequence Type ◽  
Resistance Pattern ◽  
Whole Genome ◽  
Drug Resistant ◽  
Nosocomial Outbreak ◽  
Content Type ◽  
Rapid Transmission ◽  
Case Presentations

ABSTRACT Streptococcus pneumoniae infections arising in hospitalized patients are often assumed to be sporadic and linked to community acquisition. Here, whole-genome sequencing was used to demonstrate nosocomial acquisition of antimicrobial-resistant sequence type 156 (ST156) serotype 9V S. pneumoniae in 3 respiratory patients that resulted in two bacteremias and one lower respiratory tract infection. Two of the cases arose in patients who had recently been discharged from the hospital and were readmitted from the community. Nosocomial spread was suspected solely because of the highly unusual resistance pattern and case presentations within 24 h of one another. The outbreak highlights the potential for rapid transmission and the short incubation period in the respiratory ward setting.

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