scholarly journals Activity of Meropenem Combined with RPX7009, a Novel β-Lactamase Inhibitor, against Gram-Negative Clinical Isolates in New York City

2015 ◽  
Vol 59 (8) ◽  
pp. 4856-4860 ◽  
Author(s):  
Amabel Lapuebla ◽  
Marie Abdallah ◽  
Olawole Olafisoye ◽  
Christopher Cortes ◽  
Carl Urban ◽  
...  
Keyword(s):  
New York ◽  
New York City ◽  
York City ◽  
Carbapenem Resistance ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Gram Negative ◽  
Content Type ◽  
Lactamase Inhibitor

ABSTRACTMultidrug-resistantKlebsiella pneumoniaecarbapenemase (KPC)-producingEnterobacteriaceaeare endemic to hospitals in New York City and other regions. RPX7009 is a novel β-lactamase inhibitor with activity against serine carbapenemases. We tested the activity of meropenem plus RPX7009 against 4,500 recent Gram-negative clinical isolates from 11 New York City hospitals. The meropenem-RPX7009 combination was found to have excellentin vitroactivity againstEscherichia coli,K. pneumoniae, andEnterobacterspp., including multidrug-resistant (MDR) KPC-producing strains. Overall, 131/133 (98.5%) KPC-producingEnterobacteriaceaestrains were inhibited by meropenem (≤1 μg/ml) plus RPX7009 (8 μg/ml). In a limited number of strains, the combination appeared to have reduced activity against KPC-producingK. pneumoniaeisolates with diminishedompK35andompK36expression. The addition of RPX7009 did not affect the activity of meropenem againstAcinetobacter baumanniiandPseudomonas aeruginosa. The meropenem-RPX7009 combination shows promise as a novel agent against KPC-producingEnterobacteriaceaeand deserves further study. Other approaches will be needed to address multidrug-resistantA. baumanniiandP. aeruginosa, which typically possess different mechanisms of carbapenem resistance.

scholarly journals Activity of Meropenem with a Novel Broader-Spectrum β-Lactamase Inhibitor, WCK 4234, against Gram-Negative Pathogens Endemic to New York City

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Alejandro Iregui ◽  
Zeb Khan ◽  
David Landman ◽  
John Quale
Keyword(s):  
New York ◽  
New York City ◽  
York City ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Gram Negative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Lactamase Inhibitor

ABSTRACT WCK 4234 is a novel diazabicyclooctane with potent inhibitory activity against class A and D carbapenemases and class C enzymes. We examined the in vitro activity of meropenem plus WCK 4234 (4 or 8 μg/ml) against Gram-negative pathogens from New York City. Three groups of isolates were analyzed: a contemporary collection of isolates, a collection of known carbapenem-resistant isolates, and a collection of isolates with defined resistance mechanisms. From the contemporary collection, we found (i) that all Enterobacteriaceae were susceptible to meropenem plus WCK 4234, (ii) that susceptibility rates for Acinetobacter baumannii were 56.5% for meropenem alone, 82.6% with 4 μg/ml WCK 4234, and 95.7% with 8 μg/ml WCK 4234, and (iii) that WCK 4234 had a modest effect on susceptibility of Pseudomonas aeruginosa. Against a collection of carbapenem-resistant isolates, the addition of WCK 4234 to meropenem (i) restored meropenem susceptibility against Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae isolates, (ii) improved susceptibility against A. baumannii, and (iii) had a negligible effect against P. aeruginosa. When tested against isolates with defined mechanisms of resistance, MICs of meropenem plus WCK 4234 were higher for K. pneumoniae with blaKPC albeit well below the susceptibility breakpoint; efflux systems or porins did not correlate with susceptibility. For A. baumannii, MICs of meropenem plus WCK 4234 did not correlate with efflux systems, outer membrane protein, blaampC, or blaoxa-51; however, MICs were higher in isolates with extended-spectrum β-lactamases (ESBLs). For P. aeruginosa, isolates with relatively higher MICs of meropenem plus WCK 4234 had increased expression of ampC. WCK 4234 is a potent β-lactamase inhibitor that, when combined with meropenem, displays promising activity against multidrug-resistant pathogens.

scholarly journals Activity of Eravacycline against Enterobacteriaceae and Acinetobacter baumannii, Including Multidrug-Resistant Isolates, from New York City

2014 ◽  
Vol 59 (3) ◽  
pp. 1802-1805 ◽  
Author(s):  
Marie Abdallah ◽  
Olawole Olafisoye ◽  
Christopher Cortes ◽  
Carl Urban ◽  
David Landman ◽  
...  
Keyword(s):  
New York ◽  
New York City ◽  
Acinetobacter Baumannii ◽  
York City ◽  
Enterobacter Aerogenes ◽  
Enterobacter Cloacae ◽  
Multidrug Resistant ◽  
Gram Negative ◽  
Content Type

ABSTRACTEravacycline demonstratedin vitroactivity against a contemporary collection of more than 4,000 Gram-negative pathogens from New York City hospitals, with MIC50/MIC90values, respectively, forEscherichia coliof 0.12/0.5 μg/ml,Klebsiella pneumoniaeof 0.25/1 μg/ml,Enterobacter aerogenesof 0.25/1 μg/ml,Enterobacter cloacae0.5/1 μg/ml, andAcinetobacter baumanniiof 0.5/1 μg/ml. Activity was retained against multidrug-resistant isolates, including those expressing KPC and OXA carbapenemases. ForA. baumannii, eravacycline MICs correlated with increased expression of theadeBgene.

scholarly journals Activity of Imipenem with Relebactam against Gram-Negative Pathogens from New York City

2015 ◽  
Vol 59 (8) ◽  
pp. 5029-5031 ◽  
Author(s):  
Amabel Lapuebla ◽  
Marie Abdallah ◽  
Olawole Olafisoye ◽  
Christopher Cortes ◽  
Carl Urban ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
New York ◽  
Pseudomonas Aeruginosa ◽  
New York City ◽  
Klebsiella Pneumoniae ◽  
York City ◽  
Multidrug Resistant ◽  
Gram Negative ◽  
Content Type ◽  
Added Benefit

ABSTRACTImipenem with relebactam was active againstEscherichia coli,Klebsiella pneumoniae, andEnterobacterspp., includingK. pneumoniaecarbapenemase (KPC)-producing isolates. Loss of OmpK36 in KPC-producingK. pneumoniaeisolates affected the susceptibility of this combination. Enhanced activity was evident againstPseudomonas aeruginosa, including isolates with depressedoprDand increasedampCexpression. However, the addition of relebactam to imipenem did not provide added benefit againstAcinetobacter baumannii. The combination of imipenem with relebactam demonstrated activity against KPC-producingEnterobacteriaceaeand multidrug-resistantP. aeruginosa.

scholarly journals Inactivation of the Pseudomonas -Derived Cephalosporinase-3 (PDC-3) by Relebactam

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Melissa D. Barnes ◽  
Christopher R. Bethel ◽  
Jim Alsop ◽  
Scott A. Becka ◽  
Joseph D. Rutter ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Gram Negative ◽  
Content Type ◽  
Life Threatening ◽  
Lactamase Inhibitor

ABSTRACT Pseudomonas aeruginosa is a prevalent and life-threatening Gram-negative pathogen. Pseudomonas -derived cephlosporinase (PDC) is the major inducible cephalosporinase in P. aeruginosa . In this investigation, we show that relebactam, a diazabicyclooctane β-lactamase inhibitor, potently inactivates PDC-3, with a k 2 / K of 41,400 M −1 s −1 and a k off of 0.00095 s −1 . Relebactam restored susceptibility to imipenem in 62% of multidrug-resistant P. aeruginosa clinical isolates, while only 21% of isolates were susceptible to imipenem-cilastatin alone. Relebactam promises to increase the efficacy of imipenem-cilastatin against P. aeruginosa .

scholarly journals Evaluation of theIn VitroActivity of Eravacycline against a Broad Spectrum of Recent Clinical Anaerobic Isolates

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
David R. Snydman ◽  
Laura A. McDermott ◽  
Nilda V. Jacobus ◽  
Kathryn Kerstein ◽  
Trudy H. Grossman ◽  
...  
Keyword(s):  
Specific Resistance ◽  
Multidrug Resistant ◽  
The Novel ◽  
Gram Negative ◽  
Content Type ◽  
Resistance Determinants ◽  
Serious Infections ◽  
Aerobic And Anaerobic ◽  
Lactamase Inhibitor

ABSTRACTThe novel fluorocycline antibiotic eravacycline is in development for use in the treatment of serious infections caused by susceptible and multidrug-resistant (MDR) aerobic and anaerobic Gram-negative and Gram-positive pathogens. Eravacycline and 11 comparator antibiotics were tested against recent anaerobic clinical isolates, including MDRBacteroidesspp. andClostridium difficile. Eravacycline was potentin vitroagainst all the isolates tested, including strains with tetracycline-specific resistance determinants and MDR anaerobic pathogens resistant to carbapenems and/or β-lactam–β-lactamase inhibitor combinations.

scholarly journals High-Level Carbapenem Resistance in a Klebsiella pneumoniae Clinical Isolate Is Due to the Combination of blaACT-1 β-Lactamase Production, Porin OmpK35/36 Insertional Inactivation, and Down-Regulation of the Phosphate Transport Porin PhoE

2006 ◽  
Vol 50 (10) ◽  
pp. 3396-3406 ◽  
Author(s):  
Frank M. Kaczmarek ◽  
Fadia Dib-Hajj ◽  
Wenchi Shang ◽  
Thomas D. Gootz
Keyword(s):  
New York ◽  
New York City ◽  
Klebsiella Pneumoniae ◽  
York City ◽  
Carbapenem Resistance ◽  
Clinical Isolates ◽  
Wild Type ◽  
Down Regulation ◽  
Carbapenem Resistant ◽  
Insertional Inactivation

ABSTRACT Clinical isolates of Klebsiella pneumoniae resistant to carbapenems and essentially all other antibiotics (multidrug resistant) are being isolated from some hospitals in New York City with increasing frequency. A highly related pair of K. pneumoniae strains isolated on the same day from one patient in a hospital in New York City were studied for antibiotic resistance. One (KP-2) was resistant to imipenem, meropenem, and sulopenem (MICs of 16 to 32 μg/ml) while the other (KP-1) was susceptible (MIC of 0.5 μg/ml); both contained the bla ACT-1, bla SHV-1, and bla TEM-1 β-lactamases. bla ACT-1 in both strains was encoded on a large ∼150-kb plasmid. Both isolates contained an identical class 1 integron encoding resistance to aminoglycosides and chloramphenicol. They each had identical insertions in ompK35 and ompK36, resulting in disruption of these key porin genes. The carbapenem-resistant and -susceptible isolates were extensively studied for differences in the structural and regulatory genes for the operons acrRAB, marORAB, romA-ramA, soxRS, micF, micC, phoE, phoBR, rpoS, and hfq. No changes were detected between the isolates except for a significant down-regulation of ompK37, phoB, and phoE in KP-2 as deduced from reverse transcription-PCR analysis of mRNA and polyacrylamide gel electrophoresis separation of outer membrane proteins. Backcross analysis was conducted using the wild-type phoE gene cloned into the vector pGEM under regulation of its native promoter as well as the lacZ promoter following transformation into the resistant KP-2 isolate. The wild-type gene reversed carbapenem resistance only when under control of the heterologous lacZ promoter. In the background of ompK35-ompK36 gene disruption, the up-regulation of phoE in KP-1 apparently compensated for porin loss and conferred carbapenem susceptibility. Down-regulation of phoE in KP-2 may represent the normal state of this gene, or it may have been selected from KP-1 in vivo under antibiotic pressure, generating the carbapenem-resistant clone. This is the first study in the Enterobacteriaceae where expression of the phosphate-regulated PhoE porin has been associated with resistance to antimicrobials. Our results with this pair of Klebsiella clinical isolates highlight the complex and evolving nature of multiple drug resistance in this species.

scholarly journals Novel Phage Lysin Capable of Killing the Multidrug-Resistant Gram-Negative Bacterium Acinetobacter baumannii in a Mouse Bacteremia Model

2015 ◽  
Vol 59 (4) ◽  
pp. 1983-1991 ◽  
Author(s):  
Rolf Lood ◽  
Benjamin Y. Winer ◽  
Adam J. Pelzek ◽  
Roberto Diez-Martinez ◽  
Mya Thandar ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Genomic Library ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Gram Negative ◽  
Content Type ◽  
Highly Active ◽  
Genes Encoding

ABSTRACTAcinetobacter baumannii, a Gram-negative multidrug-resistant (MDR) bacterium, is now recognized as one of the more common nosocomial pathogens. Because most clinical isolates are found to be multidrug resistant, alternative therapies need to be developed to control this pathogen. We constructed a bacteriophage genomic library based on prophages induced from 13A. baumanniistrains and screened it for genes encoding bacteriolytic activity. Using this approach, we identified 21 distinct lysins with different activities and sequence diversity that were capable of killingA. baumannii. The lysin (PlyF307) displaying the greatest activity was further characterized and was shown to efficiently kill (>5-log-unit decrease) all testedA. baumanniiclinical isolates. Treatment with PlyF307 was able to significantly reduce planktonic and biofilmA. baumanniibothin vitroandin vivo. Finally, PlyF307 rescued mice from lethalA. baumanniibacteremia and as such represents the first highly active therapeutic lysin specific for Gram-negative organisms in an array of native lysins found inAcinetobacterphage.

scholarly journals WCK 5222 (Cefepime-Zidebactam) Antimicrobial Activity against Clinical Isolates of Gram-Negative Bacteria Collected Worldwide in 2015

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Helio S. Sader ◽  
Mariana Castanheira ◽  
Michael Huband ◽  
Ronald N. Jones ◽  
Robert K. Flamm
Keyword(s):  
Antimicrobial Activity ◽  
Bacterial Infections ◽  
The United States ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Asia Pacific ◽  
Gram Negative ◽  
Content Type ◽  
Broth Microdilution Method

ABSTRACT WCK 5222 consists of cefepime combined with zidebactam, a bicyclo-acyl hydrazide β-lactam enhancer antibiotic with a dual action involving binding to Gram-negative bacterial PBP2 and β-lactamase inhibition. We evaluated the in vitro activity of cefepime-zidebactam against 7,876 contemporary (2015) clinical isolates of Enterobacteriaceae (n = 5,946), Pseudomonas aeruginosa (n = 1,291), and Acinetobacter spp. (n = 639) from the United States (n = 2,919), Europe (n = 3,004), the Asia-Pacific (n = 1,370), and Latin America (n = 583). The isolates were tested by a reference broth microdilution method for susceptibility against cefepime-zidebactam (1:1 and 2:1 ratios) and comparator agents. Cefepime-zidebactam was the most active compound tested against Enterobacteriaceae (MIC50/90, ≤0.03/0.12 μg/ml [1:1] and 0.06/0.25 μg/ml [2:1]; 99.9% of isolates were inhibited at ≤4 [1:1] and ≤8 μg/ml [2:1]). Cefepime-zidebactam was active against individual Enterobacteriaceae species (MIC50/90, ≤0.03 to 0.06/≤0.03 to 0.5 μg/ml [1:1]) and retained potent activity against carbapenem-resistant isolates (MIC50/90, 1/4 μg/ml; 99.3% of isolates were inhibited at ≤8 μg/ml [1:1]). Cefepime-zidebactam activity was consistent among geographic regions, and only one isolate showed MIC values of >8 μg/ml (1:1). Cefepime-zidebactam was also very active against P. aeruginosa with MIC50/90 values of 1/4 μg/ml, and 99.5% of isolates were inhibited at ≤8 μg/ml (1:1). The MIC values for cefepime-zidebactam at the 1:1 ratio were generally 2-fold lower than those for cefepime-zidebactam at the 2:1 ratio (MIC50/90, 2/8 μg/ml) and zidebactam alone (MIC50/90, 4/8 μg/ml). Against Acinetobacter spp., cefepime-zidebactam at 1:1 and 2:1 ratios (MIC50/90, 16/32 μg/ml for both) was 4-fold more active than cefepime or ceftazidime. Zidebactam exhibited potent in vitro antimicrobial activity against some organisms. These results support the clinical development of WCK 5222 for the treatment of Gram-negative bacterial infections, including those caused by multidrug-resistant isolates.

scholarly journals In Vitro Activity of Cefiderocol, a Siderophore Cephalosporin, against Multidrug-Resistant Gram-Negative Bacteria

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
Shazad Mushtaq ◽  
Zahra Sadouki ◽  
Anna Vickers ◽  
David M. Livermore ◽  
Neil Woodford
Keyword(s):  
Dipicolinic Acid ◽  
Carbapenem Resistance ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
In Vitro Activity ◽  
Gram Negative ◽  
Content Type ◽  
Mueller Hinton ◽  
Mueller Hinton Broth

ABSTRACT Cefiderocol is a parenteral siderophore cephalosporin with a catechol-containing 3′ substituent. We evaluated its MICs against Gram-negative bacteria, using iron-depleted Mueller-Hinton broth. The panel comprised 305 isolates of Enterobacterales, 111 of Pseudomonas aeruginosa, and 99 of Acinetobacter baumannii, all selected for carbapenem resistance and multidrug resistance to other agents. At 2 and 4 μg/ml, cefiderocol inhibited 78.7 and 92.1%, respectively, of all Enterobacterales isolates tested, with rates of 80 to 100% for isolates with all modes of carbapenem resistance except NDM enzymes (41.0% inhibited at 2 μg/ml and 72.1% at 4 μg/ml) or combinations of extended-spectrum β-lactamase (ESBL) and porin loss (61.5% inhibited at 2 μg/ml and 88.5% at 4 μg/ml). Cefiderocol also inhibited 81.1 and 86.5% of all P. aeruginosa isolates at 2 and 4 μg/ml, respectively, with rates of 80 to 100% for isolates with VIM, IMP, GES, or VEB β-lactamases and slightly lower rates for those with NDM (45.5% at 2 μg/ml and 72.7% at 4 μg/ml) and PER (66.7% at 2 μg/ml and 73.3% at 4 μg/ml) enzymes; 63.3% of P. aeruginosa isolates were inhibited at the FDA’s 1-μg/ml breakpoint. Lastly, cefiderocol at 2 and 4 μg/ml inhibited 80.8 and 88.9% of the A. baumannii isolates, respectively, with rates of >85% for isolates with OXA-51-like, -23, -24, or -58 enzymes and 50% at 2 μg/ml and 80% at 4 μg/ml for those with NDM carbapenemases. Dipicolinic acid and avibactam weakly potentiated cefiderocol against Enterobacterales isolates with metallo-β-lactamases (MBLs) and serine carbapenemase, respectively, indicating incomplete β-lactamase stability.

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