scholarly journals Therapeutic Efficacy of Novel Antimicrobial Peptide AA139-Nanomedicines in a Multidrug-Resistant Klebsiella pneumoniae Pneumonia-Septicemia Model in Rats

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Hessel van der Weide ◽  
Unai Cossío ◽  
Raquel Gracia ◽  
Yvonne M. te Welscher ◽  
Marian T. ten Kate ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Therapeutic Efficacy ◽  
Antimicrobial Agents ◽  
Polymeric Nanoparticles ◽  
Multidrug Resistant ◽  
Antimicrobial Activities ◽  
Bacterial Killing ◽  
Gram Negative ◽  
Content Type

ABSTRACT Antimicrobial peptides (AMPs) have seen limited clinical use as antimicrobial agents, largely due to issues relating to toxicity, short biological half-life, and lack of efficacy against Gram-negative bacteria. However, the development of novel AMP-nanomedicines, i.e., AMPs entrapped in nanoparticles, has the potential to ameliorate these clinical problems. The authors investigated two novel nanomedicines based on AA139, an AMP currently in development for the treatment of multidrug-resistant Gram-negative infections. AA139 was entrapped in polymeric nanoparticles (PNPs) or lipid-core micelles (MCLs). The antimicrobial activity of AA139-PNP and AA139-MCL was determined in vitro. The biodistribution and limiting doses of AA139-nanomedicines were determined in uninfected rats via endotracheal aerosolization. The early bacterial killing activity of the AA139-nanomedicines in infected lungs was assessed in a rat model of pneumonia-septicemia caused by extended-spectrum β-lactamase-producing Klebsiella pneumoniae. In this model, the therapeutic efficacy was determined by once-daily (q24h) administration over 10 days. Both AA139-nanomedicines showed equivalent in vitro antimicrobial activities (similar to free AA139). In uninfected rats, they exhibited longer residence times in the lungs than free AA139 (∼20% longer for AA139-PNP and ∼80% longer for AA139-MCL), as well as reduced toxicity, enabling a higher limiting dose. In rats with pneumonia-septicemia, both AA139-nanomedicines showed significantly improved therapeutic efficacy in terms of an extended rat survival time, although survival of all rats was not achieved. These results demonstrate potential advantages that can be achieved using AMP-nanomedicines. AA139-PNP and AA139-MCL may be promising novel therapeutic agents for the treatment of patients suffering from multidrug-resistant Gram-negative pneumonia-septicemia.

scholarly journals In VitroActivity of Plazomicin against Gram-Negative and Gram-Positive Bacterial Pathogens Isolated from Patients in Canadian Hospitals from 2013 to 2017 as Part of the CANWARD Surveillance Study

2018 ◽  
Vol 63 (1) ◽  
Author(s):  
Andrew Walkty ◽  
James A. Karlowsky ◽  
Melanie R. Baxter ◽  
Heather J. Adam ◽  
George G. Zhanel
Keyword(s):  
Antimicrobial Agents ◽  
Bacterial Pathogens ◽  
Multidrug Resistant ◽  
Surveillance Study ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Microdilution Method ◽  
Broth Microdilution Method

ABSTRACTThe Clinical and Laboratory Standards Institute (CLSI) broth microdilution method was used to evaluate thein vitroactivities of plazomicin and comparator antimicrobial agents against 7,712 Gram-negative and 4,481 Gram-positive bacterial pathogens obtained from 2013 to 2017 from patients in Canadian hospitals as part of the CANWARD Surveillance Study. Plazomicin demonstrated potentin vitroactivity againstEnterobacteriaceae(MIC90≤ 1 µg/ml for all species tested exceptProteus mirabilisandMorganella morganii), including aminoglycoside-nonsusceptible, extended-spectrum β-lactamase (ESBL)-positive, and multidrug-resistant (MDR) isolates. Plazomicin was equally active against methicillin-susceptible and methicillin-resistant isolates ofStaphylococcus aureus.

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

2020 ◽  
Vol 64 (12) ◽  
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.

scholarly journals In Vitro Activity of Imipenem-Relebactam against Gram-Negative ESKAPE Pathogens Isolated by Clinical Laboratories in the United States in 2015 (Results from the SMART Global Surveillance Program)

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Sibylle H. Lob ◽  
Meredith A. Hackel ◽  
Krystyna M. Kazmierczak ◽  
Katherine Young ◽  
Mary R. Motyl ◽  
...  
Keyword(s):  
United States ◽  
Klebsiella Pneumoniae ◽  
Antimicrobial Agents ◽  
The United States ◽  
Surveillance Program ◽  
Gram Negative ◽  
Content Type ◽  
Clinical Laboratories ◽  
Eskape Pathogens

ABSTRACT Relebactam (formerly MK-7655) is an inhibitor of class A and C β-lactamases, including Klebsiella pneumoniae carbapenemase (KPC), and is currently in clinical development in combination with imipenem-cilastatin. Using Clinical and Laboratory Standards Institute (CLSI)-defined broth microdilution methodology, we evaluated the in vitro activities of imipenem-relebactam, imipenem, and seven routinely tested parenteral antimicrobial agents against Gram-negative ESKAPE pathogens (including Klebsiella pneumoniae, n = 689; Acinetobacter baumannii, n = 72; Pseudomonas aeruginosa, n = 845; and Enterobacter spp., n = 399) submitted by 21 clinical laboratories in the United States in 2015 as part of the SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance program. Relebactam was tested at a fixed concentration of 4 μg/ml in combination with doubling dilutions of imipenem. Imipenem-relebactam MICs were interpreted using CLSI imipenem breakpoints. The respective rates of susceptibility to imipenem-relebactam and imipenem were 94.2% (796/845) and 70.3% (594/845) for P. aeruginosa, 99.0% (682/689) and 96.1% (662/689) for K. pneumoniae, and 100% (399/399) and 98.0% (391/399) for Enterobacter spp. Relebactam restored imipenem susceptibility to 80.5% (202/251), 74.1% (20/27), and 100% (8/8) of isolates of imipenem-nonsusceptible P. aeruginosa, K. pneumoniae, and Enterobacter spp. Relebactam did not increase the number of isolates of Acinetobacter spp. susceptible to imipenem, and the rates of resistance to all of the agents tested against this pathogen were >30%. Further development of imipenem-relebactam is warranted given the demonstrated ability of relebactam to restore the activity of imipenem against current clinical isolates of Enterobacteriaceae and P. aeruginosa that are nonsusceptible to carbapenems and its potential as a therapy for treating patients with antimicrobial-resistant Gram-negative infections.

scholarly journals Comparative In Vivo Antibacterial Activity of Human-Simulated Exposures of Cefiderocol and Ceftazidime against Stenotrophomonas maltophilia in the Murine Thigh Model

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Iris H. Chen ◽  
James M. Kidd ◽  
Kamilia Abdelraouf ◽  
David P. Nicolau
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Multidrug Resistant ◽  
Bacterial Reduction ◽  
Bacterial Killing ◽  
Gram Negative ◽  
Content Type ◽  
Log Reduction ◽  
Gram Negative Organisms

ABSTRACT Cefiderocol is a novel siderophore cephalosporin that utilizes bacterial ferric iron transports to cross the outer membrane. Cefiderocol shows high stability against all classes of β-lactamases, rendering it extremely potent against carbapenem- and multidrug-resistant Gram-negative organisms. Using a neutropenic murine thigh model, we compared the efficacies of human-simulated exposures of cefiderocol (20-g, 3-h infusion every 8 h [Q8H]) and ceftazidime (2-g, 2-h infusion Q8H) against Stenotrophomonas maltophilia, an emerging opportunistic Gram-negative organism associated with serious and often fatal nosocomial infections. Twenty-four S. maltophilia isolates were studied, including isolates resistant to ceftazidime, trimethoprim-sulfate, and/or levofloxacin. The thighs were inoculated with bacterial suspensions of 108 CFU/ml, and the human-simulated regimens were administered over 24 h. Efficacy was measured as the change in log10 CFU/thigh at 24 h compared to 0-h controls. Cefiderocol human-simulated exposure demonstrated potent bacterial killing; the mean bacterial reduction at 24 h was −2.67 ± 0.68 log10 CFU/thigh with ≥2-log reduction achieved in 21 isolates (87.5%) and a ≥1-log reduction achieved in the remaining 3 isolates (12.5%). In comparison, ceftazidime human-simulated exposure produced a mean bacterial reduction of −1.38 ± 1.49 log10 CFU/thigh among 10 ceftazidime-susceptible isolates and a mean bacterial growth of 0.64 ± 0.79 log10 CFU/thigh among 14 ceftazidime-nonsusceptible isolates. Although ceftazidime showed modest efficacy against most susceptible isolates, humanized cefiderocol exposures resulted in remarkable in vivo activity against all S. maltophilia isolates examined, inclusive of ceftazidime-nonsusceptible isolates. The potent in vitro and in vivo activity of cefiderocol supports the development of this novel compound for managing S. maltophilia infections.

scholarly journals The Combination of Colistin and Doripenem Is Synergistic against Klebsiella pneumoniae at Multiple Inocula and Suppresses Colistin Resistance in anIn VitroPharmacokinetic/Pharmacodynamic Model

2012 ◽  
Vol 56 (10) ◽  
pp. 5103-5112 ◽  
Author(s):  
Zakuan Z. Deris ◽  
Heidi H. Yu ◽  
Kathryn Davis ◽  
Rachel L. Soon ◽  
Jovan Jacob ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Population Analysis ◽  
Multidrug Resistant ◽  
Pharmacodynamic Model ◽  
Resistant Isolate ◽  
Colistin Resistance ◽  
Bacterial Killing ◽  
Content Type

ABSTRACTMultidrug-resistant (MDR)Klebsiella pneumoniaemay require combination therapy. We systematically investigated bacterial killing with colistin and doripenem mono- and combination therapy against MDRK. pneumoniaeand emergence of colistin resistance. A one-compartmentin vitropharmacokinetic/pharmacodynamic model was employed over a 72-h period with two inocula (∼106and ∼108CFU/ml); a colistin-heteroresistant reference strain (ATCC 13883) and three clinical isolates (colistin-susceptible FADDI-KP032 [doripenem resistant], colistin-heteroresistant FADDI-KP033, and colistin-resistant FADDI-KP035) were included. Four combinations utilizing clinically achievable concentrations were investigated. Microbiological responses were examined by determining log changes and population analysis profiles (for emergence of colistin resistance) over 72 h. Against colistin-susceptible and -heteroresistant isolates, combinations of colistin (constant concentration regimens of 0.5 or 2 mg/liter) plus doripenem (steady-state peak concentration [Cmax] of 2.5 or 25 mg/liter over 8 h; half-life, 1.5 h) generally resulted in substantial improvements in bacterial killing at both inocula. Combinations were additive or synergistic against ATCC 13883, FADDI-KP032, and FADDI-KP033 in 9, 9, and 14 of 16 cases (4 combinations at 6, 24, 48, and 72 h) at the 106-CFU/ml inoculum and 14, 11, and 12 of 16 cases at the 108-CFU/ml inoculum, respectively. Combinations at the highest dosage regimens resulted in undetectable bacterial counts at 72 h in 5 of 8 cases (4 isolates at 2 inocula). Emergence of colistin-resistant subpopulations in colistin-susceptible and -heteroresistant isolates was virtually eliminated with combination therapy. Against the colistin-resistant isolate, colistin at 2 mg/liter plus doripenem (Cmax, 25 mg/liter) at the low inoculum improved bacterial killing. This investigation provides important information for optimization of colistin-doripenem combinations.

scholarly journals In Vitro Activity of Eravacycline against Gram-Negative Bacilli Isolated in Clinical Laboratories Worldwide from 2013 to 2017

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Ian Morrissey ◽  
Melanie Olesky ◽  
Stephen Hawser ◽  
Sibylle H. Lob ◽  
James A. Karlowsky ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Gram Negative ◽  
Content Type ◽  
Microdilution Method ◽  
Clinical Laboratories ◽  
Serious Infections ◽  
Broth Microdilution Method

ABSTRACT Eravacycline is a novel, fully synthetic fluorocycline antibiotic developed for the treatment of serious infections, including those caused by multidrug-resistant (MDR) pathogens. Here, we evaluated the in vitro activities of eravacycline and comparator antimicrobial agents against a global collection of frequently encountered clinical isolates of Gram-negative bacilli. The CLSI broth microdilution method was used to determine MIC data for isolates of Enterobacterales (n = 13,983), Acinetobacter baumannii (n = 2,097), Pseudomonas aeruginosa (n = 1,647), and Stenotrophomonas maltophilia (n = 1,210) isolated primarily from respiratory, intra-abdominal, and urinary specimens by clinical laboratories in 36 countries from 2013 to 2017. Susceptibilities were interpreted using both CLSI and EUCAST breakpoints. Multidrug-resistant (MDR) isolates were defined by resistance to agents from ≥3 different antimicrobial classes. The MIC90s ranged from 0.25 to 1 μg/ml for Enterobacteriaceae and were 1 μg/ml for A. baumannii and 2 μg/ml for S. maltophilia, Proteus mirabilis, and Serratia marcescens. Eravacycline’s potency was up to 4-fold greater than that of tigecycline against genera/species of Enterobacterales, A. baumannii, and S. maltophilia. The MIC90s for five of six individual genera/species of Enterobacterales and A. baumannii were within 2-fold of the MIC90s for their respective subsets of MDR isolates, while the MDR subpopulation of Klebsiella spp. demonstrated 4-fold higher MIC90s. Eravacycline demonstrated potent in vitro activity against the majority of clinical isolates of Gram-negative bacilli, including MDR isolates, collected over a 5-year period. This study further underscores the potential benefit of eravacycline in the treatment of infections caused by MDR Gram-negative pathogens.

scholarly journals Isolation and Characterization of Novel Phages Targeting Pathogenic Klebsiella pneumoniae

2021 ◽  
Vol 11 ◽  
Author(s):  
Na Li ◽  
Yigang Zeng ◽  
Rong Bao ◽  
Tongyu Zhu ◽  
Demeng Tan ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
S1 Nuclease ◽  
Isolation And Characterization ◽  
Comprehensive Knowledge ◽  
Future Challenges ◽  
Lactamase Gene

Klebsiella pneumoniae is a dominant cause of community-acquired and nosocomial infections, specifically among immunocompromised individuals. The increasing occurrence of multidrug-resistant (MDR) isolates has significantly impacted the effectiveness of antimicrobial agents. As antibiotic resistance is becoming increasingly prevalent worldwide, the use of bacteriophages to treat pathogenic bacterial infections has recently gained attention. Elucidating the details of phage-bacteria interactions will provide insights into phage biology and the better development of phage therapy. In this study, a total of 22 K. pneumoniae isolates were assessed for their genetic and phenotypic relatedness by multi-locus sequence typing (MLST), endonuclease S1 nuclease pulsed-field gel electrophoresis (S1-PFGE), and in vitro antibiotic susceptibility testing. In addition, the beta-lactamase gene (blaKPC) was characterized to determine the spread and outbreak of K. pneumoniae carbapenemase (KPC)-producing enterobacterial pathogens. Using these ST11 carbapenem-resistant K. pneumoniae isolates, three phages (NL_ZS_1, NL_ZS_2, and NL_ZS_3) from the family of Podoviridae were isolated and characterized to evaluate the application of lytic phages against the MDR K. pneumoniae isolates. In vitro inhibition assays with three phages and K. pneumoniae strain ZS15 demonstrated the strong lytic potential of the phages, however, followed by the rapid growth of phage-resistant and phage-sensitive mutants, suggesting several anti-phage mechanisms had developed in the host populations. Together, this data adds more comprehensive knowledge to known phage biology and further emphasizes their complexity and future challenges to overcome prior to using phages for controlling this important MDR bacterium.

scholarly journals In vitro synergy of 5-nitrofurans, vancomycin and sodium deoxycholate against Gram-negative pathogens

2021 ◽  
Author(s):  
Catrina Olivera ◽  
Vuong Van Hung Le ◽  
Catherine Davenport ◽  
Jasna Rakonjac
Keyword(s):  
Growth Inhibition ◽  
Type Species ◽  
Sodium Deoxycholate ◽  
Gram Positive ◽  
Bacterial Killing ◽  
Gram Negative ◽  
Content Type ◽  
Link Type ◽  
Time Kill

Introduction. There is an urgent need for effective therapies against bacterial infections, especially those caused by antibiotic-resistant Gram-negative pathogens. Hypothesis. Synergistic combinations of existing antimicrobials show promise due to their enhanced efficacies and reduced dosages which can mitigate adverse effects, and therefore can be used as potential antibacterial therapy. Aim. In this study, we sought to characterize the in vitro interaction of 5-nitrofurans, vancomycin and sodium deoxycholate (NVD) against pathogenic bacteria. Methodology. The synergy of the NVD combination was investigated in terms of growth inhibition and bacterial killing using checkerboard and time-kill assays, respectively. Results. Using a three-dimensional checkerboard assay, we showed that 5-nitrofurans, sodium deoxycholate and vancomycin interact synergistically in the growth inhibition of 15 out of 20 Gram-negative strains tested, including clinically significant pathogens such as carbapenemase-producing Escherichia coli , Klebsiella pneumoniae and Acinetobacter baumannii , and interact indifferently against the Gram-positive strains tested. The time-kill assay further confirmed that the triple combination was bactericidal in a synergistic manner. Conclusion. This study demonstrates the synergistic effect of 5-nitrofurans, sodium deoxycholate and vancomycin against Gram-negative pathogens and highlights the potential of the combination as a treatment for Gram-negative and Gram-positive infections.

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

2015 ◽  
Vol 59 (4) ◽  
pp. 2280-2285 ◽  
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.

scholarly journals 519. Multidrug-resistant Gram-Negative Bacteremia in Pediatric Patients: Is It Time to Change to Empiric Meropenem?

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S250-S250
Author(s):  
Kanokporn Mongkolrattanothai ◽  
Leslie Stach ◽  
Regina Orbach
Keyword(s):  
Antimicrobial Agents ◽  
Pediatric Patients ◽  
Multidrug Resistant ◽  
Suspected Sepsis ◽  
In Vitro Susceptibility ◽  
Gram Negative ◽  
Gram Negative Bacteremia ◽  
Delayed Initiation ◽  
Poor Outcomes

Abstract Background The rise of antimicrobial resistance among gram-negative (GN) pathogens has been dramatic nationally. Delayed initiation of active antimicrobial agents has been associated with poor outcomes. We aimed at evaluating the prevalence and treatment of multi-drug-resistant gram-negative (MDR-GN) bacteremia in our pediatric patients. Methods All episodes of GN bacteremia from 2017–2018 at our institution were retrospectively reviewed. GN defined as MDR in our study were carbapenem-resistant organisms (CRO), extended-spectrum β-lactamase (ESBL) producers, and GN that were resistant to cefepime and ≥2 classes of non-cephalosporin antimicrobial agents. Stenotrophomonas maltophilia was excluded. Ineffective empirical treatment (IET) is defined as an initial antibiotic regimen that is not active against the identified pathogen[s] based on in vitro susceptibility testing results. Results A total of 292 episodes of GN bacteremia were identified and 6 S. maltophilia were excluded. Of these, 29 bacteremic episodes in 26 patients were caused by MDR-GN organisms including 18 ESBL, 7 CRO, 1 ESBL and CRO, 3 non-ESBL/non-CRO cefepime-resistant MDR-GN. None of the CRO had carbapenemase genes detected. However, there was a patient with multiple sites of infection simultaneously with non-NDM CR Acinetobacter bacteremia and NDM-mediated CR-Klebsiella ventriculitis. The annual rate of MDR-GN bacteremia increased from 8% in 2017 to 12% in 2018. Almost half (48%) of episodes were community onset. Among these, all but one had underlying medical conditions with hospital exposure and most patients had central venous devices at the time of infection. 52% (15/29) episodes of MDR-GN bacteremia had IET. Despite IET, 47% (7/15) had negative blood cultures prior to initiation of effective therapy (6 ESBL and 1 P. aeruginosa). Various antibiotic regimens were used for CRO therapy as shown in Table 1. Conclusion In our institution, MDR-GN infection is increasing. As such, empiric meropenem is currently recommended in BMT or neutropenic patients with suspected sepsis. However, empiric meropenem must be used judiciously as its widely use will lead to more selection of MDR pathogens. It is essential to continue monitoring of these MDR-GN to guide appropriate empiric regimens. Disclosures All authors: No reported disclosures.

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