Clinical Experience of Colistin-Glycopeptide Combination in Critically Ill Patients Infected with Gram-Negative Bacteria

ABSTRACTA colistin-glycopeptide combination (CGC) has been shownin vitroto be synergistic against multidrug-resistant Gram-negative bacteria (MDR GNB), especiallyAcinetobacter baumannii, and to prevent further resistance. However, clinical data are lacking. We carried out a retrospective multicenter study of patients hospitalized in intensive care units (ICUs) who received colistin for GNB infection over a 1-year period, to assess the rates of nephrotoxicity and 30-day mortality after treatment onset among patients treated with and without CGC for ≥48 h. Of the 184 patients treated with colistin, GNB infection was documented for 166. The main causative agents were MDRA. baumannii(59.6%), MDRPseudomonas aeruginosa(18.7%), and carbapenem-resistantKlebsiella pneumoniae(14.5%); in 16.9% of patients, a Gram-positive bacterium (GPB) coinfection was documented. Overall, 68 patients (40.9%) received CGC. Comparison of patients treated with and without CGC showed significant differences for respiratory failure (39.7% versus 58.2%), ventilator-associated pneumonia (54.4% versus 71.4%), MDRA. baumanniiinfection (70.6% versus 52%), and GPB coinfection (41.2% versus 0%); there were no differences for nephrotoxicity (11.8% versus 13.3%) and 30-day mortality (33.8% versus 29.6%). Cox analysis performed on patients who survived for ≥5 days after treatment onset showed that the Charlson index (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.01 to 1.44;P= 0.001) and MDRA. baumanniiinfection (HR, 2.51; 95% CI, 1.23 to 5.12;P= 0.01) were independent predictors of 30-day mortality, whereas receiving CGC for ≥5 days was a protective factor (HR, 0.42; 95% CI, 0.19 to 0.93;P= 0.03). We found that CGC was not associated with higher nephrotoxicity and was a protective factor for mortality if administered for ≥5 days.

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Cefiderocol: A new cephalosporin stratagem against multidrug resistant gram-negative bacteria

Clinical Infectious Diseases ◽

10.1093/cid/ciab757 ◽

2021 ◽

Author(s):

Sharon Ong’uti ◽

Mary Czech ◽

Elizabeth Robilotti ◽

Marisa Holubar

Keyword(s):

Clinical Trials ◽

Multidrug Resistant ◽

Cell Entry ◽

Phase Iii ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Phase Iii Clinical Trials ◽

Carbapenem Resistant ◽

Tract Infections

Abstract Cefiderocol is a novel injectable siderophore cephalosporin which hijacks the bacterial iron transport machinery to facilitate cell entry and achieve high periplasmic concentrations. It has broad in vitro activity against gram-negative bacteria, including multidrug resistant (MDR) organisms like carbapenem resistant Enterobacterales (CRE), carbapenem resistant Pseudomonas aeruginosa and Acinetobacter baumannii. It was approved by the Food and Drug Administration (FDA) for the treatment of complicated urinary tract infections and nosocomial pneumonia based on clinical trials demonstrating noninferiority to comparators. In this review, we summarize the available in vitro and clinical data, including recent evidence from 2 phase III clinical trials (APEKS-NP and CREDIBLE-CR), and discuss the place of cefiderocol in the clinician’s armamentarium against MDR gram-negative infections.

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Efficacy of Humanized Exposures of Cefiderocol (S-649266) against a Diverse Population of Gram-Negative Bacteria in a Murine Thigh Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01022-17 ◽

2017 ◽

Vol 61 (11) ◽

Cited By ~ 35

Author(s):

Marguerite L. Monogue ◽

Masakatsu Tsuji ◽

Yoshinori Yamano ◽

Roger Echols ◽

David P. Nicolau

Keyword(s):

Antibacterial Activity ◽

Multidrug Resistant ◽

Infection Model ◽

Gram Negative Bacteria ◽

Diverse Population ◽

Gram Negative ◽

Content Type ◽

Log Reduction

ABSTRACT Cefiderocol (S-649266) is a novel siderophore cephalosporin with potent in vitro activity against clinically encountered multidrug-resistant (MDR) Gram-negative isolates; however, its spectrum of antibacterial activity against these difficult-to-treat isolates remains to be fully explored in vivo. Here, we evaluated the efficacy of cefiderocol humanized exposures in a neutropenic murine thigh model to support a suitable MIC breakpoint. Furthermore, we compared cefiderocol's efficacy with humanized exposures of meropenem and cefepime against a subset of these phenotypically diverse isolates. Ninety-five Gram-negative isolates were studied. Efficacy was determined as the change in log10 CFU at 24 h compared with 0-h controls. Bacterial stasis or ≥1 log reduction in 67 isolates with MICs of ≤4 μg/ml was noted in 77, 88, and 85% of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa, respectively. For isolates with MICs of ≥8 μg/ml, bacterial stasis or ≥1 log10 reduction was observed in only 2 of 28 (8 Enterobacteriaceae, 19 A. baumannii, and 1 P. aeruginosa) strains. Against highly resistant meropenem and cefepime organisms, cefiderocol maintained its in vivo efficacy. Overall, humanized exposures of cefiderocol produced similar reductions in bacterial density for organisms with MICs of ≤4 μg/ml, whereas isolates with MICs of ≥8 μg/ml generally displayed bacterial growth in the presence of the compound. Data derived in the current study will assist with the delineation of MIC susceptibility breakpoints for cefiderocol against these important nosocomial Gram-negative pathogens; however, additional clinical data are required to substantiate these observations.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01666-19 ◽

2019 ◽

Vol 64 (1) ◽

Cited By ~ 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.

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In Vitro Activity of WCK 5222 (Cefepime-Zidebactam) against Worldwide Collected Gram-Negative Bacilli Not Susceptible to Carbapenems

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01432-20 ◽

2020 ◽

Vol 64 (12) ◽

Cited By ~ 1

Author(s):

James A. Karlowsky ◽

Meredith A. Hackel ◽

Samuel K. Bouchillon ◽

Daniel F. Sahm

Keyword(s):

Antimicrobial Agents ◽

Multidrug Resistant ◽

Limiting Factor ◽

Gram Negative ◽

Content Type ◽

Microdilution Method ◽

Carbapenem Resistant ◽

Broth Microdilution Method ◽

Universal Stability

ABSTRACT WCK 5222 (cefepime-zidebactam, 2 g + 1g, every 8 h [q8h]) is in clinical development for the treatment of infections caused by carbapenem-resistant and multidrug-resistant (MDR) Gram-negative bacilli. We determined the in vitro susceptibility of 1,385 clinical isolates of non-carbapenem-susceptible Enterobacterales, MDR Pseudomonas aeruginosa (also non-carbapenem susceptible), Stenotrophomonas maltophilia, and Burkholderia spp. collected worldwide (49 countries) from 2014 to 2016 to cefepime-zidebactam (1:1 ratio), ceftazidime-avibactam, imipenem-relebactam, ceftolozane-tazobactam, and colistin using the CLSI broth microdilution method. Cefepime-zidebactam inhibited 98.5% of non-carbapenem-susceptible Enterobacterales (n = 1,018) at ≤8 μg/ml (provisional cefepime-zidebactam-susceptible MIC breakpoint). Against the subset of metallo-β-lactamase (MBL)-positive Enterobacterales (n = 214), cefepime-zidebactam inhibited 94.9% of isolates at ≤8 μg/ml. Further, it inhibited 99.6% of MDR P. aeruginosa (n = 262) isolates at ≤32 μg/ml (proposed cefepime-zidebactam-susceptible pharmacokinetic/pharmacodynamic MIC breakpoint), including all MBL-positive isolates (n = 94). Moreover, cefepime-zidebactam was active against the majority of isolates of Enterobacterales (≥95%) and P. aeruginosa (99%) that were not susceptible to ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, and colistin. Most isolates (99%) of S. maltophilia (n = 101; MIC50, 8 μg/ml; MIC90, 32 μg/ml) and Burkholderia spp. (n = 4; MIC range, 16 to 32 μg/ml) were also inhibited by cefepime-zidebactam at ≤32 μg/ml. The activity of cefepime-zidebactam against carbapenem-resistant Gram-negative bacteria is ascribed to its β-lactam enhancer mechanism of action (i.e., zidebactam binding to penicillin binding protein 2 [PBP2] and its universal stability to both serine β-lactamases and MBLs). The results from this study support the continued development of cefepime-zidebactam as a potential therapy for infections caused by Enterobacterales, P. aeruginosa, and other nonfermentative Gram-negative bacilli where resistance to marketed antimicrobial agents is a limiting factor.

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Evaluation of the Revogene Carba C Assay for Detection and Differentiation of Carbapenemase-Producing Gram-Negative Bacteria

Journal of Clinical Microbiology ◽

10.1128/jcm.01927-19 ◽

2020 ◽

Vol 58 (4) ◽

Cited By ~ 2

Author(s):

Delphine Girlich ◽

Marine Laguide ◽

Laurent Dortet ◽

Thierry Naas

Keyword(s):

Pseudomonas Aeruginosa ◽

Nucleic Acid ◽

Sensitivity And Specificity ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Microbiology Laboratory ◽

Bacterial Host ◽

Gram Negative ◽

Content Type

ABSTRACT The Revogene Carba C assay (formerly GenePOC Carba assay) is a multiplex nucleic acid-based in vitro diagnostic test intended for the detection of carbapenemase-producing Enterobacterales (CPE) from cultured colonies. This assay was evaluated directly on colonies of 118 well-characterized Enterobacterales with reduced susceptibility to carbapenems and on 49 multidrug-resistant (MDR) Pseudomonas aeruginosa and 40 MDR Acinetobacter baumannii isolates. The Revogene Carba C assay’s performance was high, as it was able to detect the five major carbapenemases (NDM, VIM, IMP, KPC, and OXA-48). In Enterobacterales, sensitivity and specificity were 100%. When extrapolating the results to the French CPE epidemiology between 2012 and 2018, this assay would have detected 99.28% of the 9,624 CPE isolates sent to the French NRC, missing 69 CPE isolates (2 GES-5, 10 OXA-23, 2 TMB-1, 1 SME-4, 53 IMI, and 1 FRI). The overall sensitivity and specificity for CP P. aeruginosa were 93.7 and 100%, respectively, as two rare IMP variants (IMP-31 and -46) were not detected. Extrapolating these results to the French epidemiology of CP P. aeruginosa in 2017, 93.3% would have been identified, missing only 1 DIM and 10 GES variants. The Revogene Carba C assay accurately identified the targeted carbapenemase genes in A. baumannii, but when extrapolating these results to the French CP A. baumannii epidemiology of 2017, only 12.50% of them could be detected, as OXA-23 is the most prevalent carbapenemase in CP A. baumannii. The Revogene Carba C assay showed excellent sensitivity and specificity for the five most common carbapenemases regardless of the bacterial host. It is well adapted to the CPE and CP P. aeruginosa epidemiology of many countries worldwide, which makes it suitable for use in the routine microbiology laboratory, with a time to result of ca. 85 min for eight isolates simultaneously.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01582-20 ◽

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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Prevention of Biofilm Colonization by Gram-Negative Bacteria on Minocycline-Rifampin-Impregnated Catheters Sequentially Coated with Chlorhexidine

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01959-13 ◽

2013 ◽

Vol 58 (2) ◽

pp. 1179-1182 ◽

Cited By ~ 26

Author(s):

Mohamed A. Jamal ◽

Joel S. Rosenblatt ◽

Ray Y. Hachem ◽

Jiang Ying ◽

Egbert Pravinkumar ◽

...

Keyword(s):

Escherichia Coli ◽

Stenotrophomonas Maltophilia ◽

Enterobacter Cloacae ◽

Central Line ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

The Novel ◽

Gram Negative ◽

Content Type

ABSTRACTResistant Gram-negative bacteria are increasing central-line-associated bloodstream infection threats. To better combat this, chlorhexidine (CHX) was added to minocycline-rifampin (M/R) catheters. Thein vitroantimicrobial activity of CHX-M/R catheters against multidrug resistant, Gram-negativeAcinetobacter baumannii,Enterobacter cloacae,Escherichia coli,Klebsiella pneumoniae,Pseudomonas aeruginosa, andStenotrophomonas maltophiliawas tested. M/R and CHX-silver sulfadiazine (CHX/SS) catheters were used as comparators. The novel CHX-M/R catheters were significantly more effective (P< 0.0001) than CHX/SS or M/R catheters in preventing biofilm colonization and showed better antimicrobial durability.

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In Vitro Properties of BAL30072, a Novel Siderophore Sulfactam with Activity against Multiresistant Gram-Negative Bacilli

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01525-09 ◽

2010 ◽

Vol 54 (6) ◽

pp. 2291-2302 ◽

Cited By ~ 152

Author(s):

Malcolm G. P. Page ◽

Clothilde Dantier ◽

Eric Desarbre

Keyword(s):

Multidrug Resistant ◽

Unusual Property ◽

Gram Negative ◽

Penicillin Binding Proteins ◽

High Affinity ◽

Class A ◽

Carbapenem Resistant ◽

Lactam Antibiotic ◽

Resistant Strains

ABSTRACT BAL30072 is a new monocyclic β-lactam antibiotic belonging to the sulfactams. Its spectrum of activity against significant Gram-negative pathogens with β-lactam-resistant phenotypes was evaluated and was compared with the activities of reference drugs, including aztreonam, ceftazidime, cefepime, meropenem, imipenem, and piperacillin-tazobactam. BAL30072 showed potent activity against multidrug-resistant (MDR) Pseudomonas aeruginosa and Acinetobacter sp. isolates, including many carbapenem-resistant strains. The MIC90s were 4 μg/ml for MDR Acinetobacter spp. and 8 μg/ml for MDR P. aeruginosa, whereas the MIC90 of meropenem for the same sets of isolates was >32 μg/ml. BAL30072 was bactericidal against both Acinetobacter spp. and P. aeruginosa, even against strains that produced metallo-β-lactamases that conferred resistance to all other β-lactams tested, including aztreonam. It was also active against many species of MDR isolates of the Enterobacteriaceae family, including isolates that had a class A carbapenemase or a metallo-β-lactamase. Unlike other monocyclic β-lactams, BAL30072 was found to trigger the spheroplasting and lysis of Escherichia coli rather than the formation of extensive filaments. The basis for this unusual property is its inhibition of the bifunctional penicillin-binding proteins PBP 1a and PBP 1b, in addition to its high affinity for PBP 3, which is the target of monobactams, such as aztreonam.

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Current Pattern and Clinico-Bacteriological Profile of Healthcare Associated Infections (HAI) in an ICU Setting: An Observational Study

10.21203/rs.3.rs-874099/v1 ◽

2021 ◽

Author(s):

Mradul Kumar Daga ◽

Govind Mawari ◽

Saman Wasi ◽

Naresh Kumar ◽

Udbhav Sharma ◽

...

Keyword(s):

Age Groups ◽

Healthcare Facility ◽

Central Line ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Healthcare Associated Infections ◽

Acinetobacter Species ◽

Gram Negative ◽

Causative Agents ◽

Healthcare Associated

Abstract Objective To understand the pattern and types of healthcare associated infections (HAI) at our healthcare facility, and to determine the common causative agents and their antibiotic susceptibility profile. Methods One hundred consecutive patients diagnosed with HAI were enrolled and monitored; the causative organisms isolated on culture were recorded and their sensitivity profile was generated. Results Of the 100 patients diagnosed with HAI (mean age ± SD being 42 ± 17 years), there were a total of 110 hospital acquired infections with 10 patients having two infections each. Out of 100 patients with HAI, 69 patients had ventilator associated pneumonia (VAP), 21 patients had catheter associated urinary tract infection (CAUTI) patients, and 20 patients had central line associated bloodstream infection (CLABSI). There were 10 patients with both VAP and CAUTI. All of the HAIs were device associated. A total of 76 pathogens were isolated on culture. No organism was isolated in 40 HAI. Majority (94.7%) of the organisms isolated from HAIs were gram-negative bacteria and all were multidrug resistant. Seventy-seven of the enrolled patients expired while 23 were discharged from the hospital Conclusions Our study demonstrated that HAIs occur in patients of all age groups; younger patients are not spared. Majority of the HAIs were caused by multidrug resistant gram-negative bacteria and were associated with high patient mortality. Acinetobacter species was the most common organism associated with HAI.

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In VitroActivity of RX-P873 against Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04840-14 ◽

2015 ◽

Vol 59 (4) ◽

pp. 2280-2285 ◽

Cited By ~ 5

Author(s):

Robert K. Flamm ◽

Paul R. Rhomberg ◽

Ronald N. Jones ◽

David J. Farrell

Keyword(s):

Pseudomonas Aeruginosa ◽

Acinetobacter Baumannii ◽

Active Agent ◽

Multidrug Resistant ◽

Surveillance Program ◽

Gram Negative ◽

Content Type ◽

Highly Active ◽

Bacterial Ribosome

ABSTRACTRX-P873 is a novel antibiotic from the pyrrolocytosine series which exhibits high binding affinity for the bacterial ribosome and broad-spectrum antibiotic properties. The pyrrolocytosines have shownin vitroactivity against multidrug-resistant Gram-negative and Gram-positive strains of bacteria known to cause complicated urinary tract, skin, and lung infections, as well as sepsis.Enterobacteriaceae(657),Pseudomonas aeruginosa(200), andAcinetobacter baumannii(202) isolates from North America and Europe collected in 2012 as part of a worldwide surveillance program were testedin vitroby broth microdilution using Clinical and Laboratory Standards Institute (CLSI) methodology. RX-P873 (MIC90, 0.5 μg/ml) was >32-fold more active than ceftazidime and inhibited 97.1% and 99.5% ofEnterobacteriaceaeisolates at MIC values of ≤1 and ≤4 μg/ml, respectively. There were only three isolates with an MIC value of >4 μg/ml (all were indole-positiveProtea). RX-P873 (MIC50/90, 2/4 μg/ml) was highly active againstPseudomonas aeruginosaisolates, including isolates which were nonsusceptible to ceftazidime or meropenem. RX-P873 was 2-fold less active againstP. aeruginosathan tobramycin (MIC90, 2 μg/ml; 91.0% susceptible) and colistin (MIC90, 2 μg/ml; 99.5% susceptible) and 2-fold more potent than amikacin (MIC90, 8 μg/ml; 93.5% susceptible) and meropenem (MIC90, 8 μg/ml; 76.0% susceptible). RX-P873, the most active agent againstAcinetobacter baumannii(MIC90, 1 μg/ml), was 2-fold more active than colistin (MIC90, 2 μg/ml; 97.0% susceptible) and 4-fold more active than tigecycline (MIC90, 4 μg/ml). This novel agent merits further exploration of its potential against multidrug-resistant Gram-negative bacteria.

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