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

2017 ◽  
Vol 61 (11) ◽  
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.

scholarly journals Therapeutic Effect and Mechanisms of the Novel Monosulfactam 0073

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Ying Sun ◽  
Xueyuan Liao ◽  
Zhigang Huang ◽  
Yaliu Xie ◽  
Yanbin Liu ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Serial Passage ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Infection Model ◽  
The Novel ◽  
Gram Negative ◽  
Content Type

ABSTRACT This study aimed to evaluate the antimicrobial activity of the novel monosulfactam 0073 against multidrug-resistant Gram-negative bacteria in vitro and in vivo and to characterize the mechanisms underlying 0073 activity. The in vitro activities of 0073, aztreonam, and the combination with avibactam were assessed by MIC and time-kill assays. The safety of 0073 was evaluated using 3-(4,5-dimethylthizol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and acute toxicity assays. Murine thigh infection and pneumonia models were employed to define in vivo efficacy. A penicillin-binding protein (PBP) competition assay and confocal microscopy were conducted. The inhibitory action of 0073 against β-lactamases was evaluated by the half-maximal inhibitory concentration (IC50), and resistance development was evaluated via serial passage. The monosulfactam 0073 showed promising antimicrobial activity against Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii isolates producing metallo-β-lactamases (MBLs) and serine β-lactamases. In preliminary experiments, compound 0073 exhibited safety both in vitro and in vivo. In the murine thigh infection model and the pneumonia models in which infection was induced by P. aeruginosa and Klebsiella pneumoniae, 0073 significantly reduced the bacterial burden. Compound 0073 targeted several PBPs and exerted inhibitory effects against some serine β-lactamases. Finally, 0073 showed a reduced propensity for resistance selection compared with that of aztreonam. The novel monosulfactam 0073 exhibited increased activity against β-lactamase-producing Gram-negative organisms compared with the activity of aztreonam and showed good safety profiles both in vitro and in vivo. The underlying mechanisms may be attributed to the affinity of 0073 for several PBPs and its inhibitory activity against some serine β-lactamases. These data indicate that 0073 represents a potential treatment for infections caused by β-lactamase-producing multidrug-resistant bacteria.

scholarly journals Antibacterial Efficacy of EravacyclineIn Vivoagainst Gram-Positive and Gram-Negative Organisms

2016 ◽  
Vol 60 (8) ◽  
pp. 5001-5005 ◽  
Author(s):  
Marguerite L. Monogue ◽  
Abrar K. Thabit ◽  
Yukihiro Hamada ◽  
David P. Nicolau
Keyword(s):  
Cumulative Dose ◽  
Dose Response ◽  
Bacterial Count ◽  
Infection Model ◽  
Gram Positive ◽  
Bacterial Killing ◽  
Gram Negative ◽  
Content Type

ABSTRACTMembers of the tetracycline class are frequently classified as bacteriostatic. However, recent findings have demonstrated an improved antibacterial killing profile, often achieving ≥3 log10bacterial count reduction, when such antibiotics have been given for periods longer than 24 h. We aimed to study this effect with eravacycline, a novel fluorocycline, given in an immunocompetent murine thigh infection model over 72 h against two methicillin-resistantStaphylococcus aureus(MRSA) isolates (eravacycline MICs = 0.03 and 0.25 μg/ml) and threeEnterobacteriaceaeisolates (eravacycline MICs = 0.125 to 0.25 μg/ml). A humanized eravacycline regimen, 2.5 mg/kg of body weight given intravenously (i.v.) every 12 h (q12h), demonstrated progressively enhanced activity over the 72-h study period. A cumulative dose response in which bacterial density was reduced by more than 3 log10CFU at 72 h was noted over the study period in the two Gram-positive isolates, and eravacycline performed similarly to comparator antibiotics (tigecycline, linezolid, and vancomycin). A cumulative dose response with eravacycline and comparators (tigecycline and meropenem) over the study period was also observed in the Gram-negative isolates, although more variability in bacterial killing was observed for all antibacterial agents. Overall, a bacterial count reduction of ≥3 log was achieved in one of the three isolates with both eravacycline and tigecycline, while meropenem achieved a similar endpoint against two of the three isolates. Bactericidal activity is typically definedin vitroover 24 h; however, extended regimen studiesin vivomay demonstrate an improved correlation with clinical outcomes by better identification of antimicrobial effects.

scholarly journals In Vitro Discordance with In Vivo Activity: Humanized Exposures of Ceftazidime-Avibactam, Aztreonam, and Tigecycline Alone and in Combination against New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae in a Murine Lung Infection Model

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
M. L. Monogue ◽  
L. M. Abbo ◽  
R. Rosa ◽  
J. F. Camargo ◽  
O. Martinez ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Lung Infection ◽  
Multidrug Resistant ◽  
Infection Model ◽  
New Delhi ◽  
Beta Lactamase ◽  
Bacterial Reduction ◽  
Content Type

ABSTRACT The management of infections with New Delhi metallo-beta-lactamase-1 (NDM)-producing bacteria remains clinically challenging given the multidrug resistant (MDR) phenotype associated with these bacteria. Despite resistance in vitro, ceftazidime-avibactam previously demonstrated in vivo activity against NDM-positive Enterobacteriaceae. Herein, we observed in vitro synergy with ceftazidime-avibactam and aztreonam against an MDR Klebsiella pneumoniae harboring NDM. In vivo, humanized doses of ceftazidime-avibactam monotherapy resulted in >2 log10 CFU bacterial reduction; therefore, no in vivo synergy was observed.

scholarly journals Activity of Cefiderocol Alone and in Combination with Levofloxacin, Minocycline, Polymyxin B, or Trimethoprim-Sulfamethoxazole against Multidrug-Resistant Stenotrophomonas maltophilia

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
M. Biagi ◽  
A. Vialichka ◽  
M. Jurkovic ◽  
T. Wu ◽  
A. Shajee ◽  
...  
Keyword(s):  
Active Site ◽  
Stenotrophomonas Maltophilia ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
First Line ◽  
Content Type ◽  
Preclinical Data ◽  
Time Kill

ABSTRACT The production of an L1 metallo-β-lactamase and an L2 serine active-site β-lactamase precludes the use of β-lactams for the treatment of Stenotrophomonas maltophilia infections. Preclinical data suggest that cefiderocol is the first approved β-lactam with reliable activity against S. maltophilia, but data on strains resistant to current first-line agents are limited, and no studies have assessed cefiderocol-based combinations. The objective of this study was to evaluate and compare the in vitro activity of cefiderocol alone and in combination with levofloxacin, minocycline, polymyxin B, or trimethoprim-sulfamethoxazole (TMP-SMZ) against a collection of highly resistant clinical S. maltophilia isolates. For this purpose, the MICs of cefiderocol, ceftazidime, levofloxacin, minocycline, polymyxin B, and TMP-SMZ for 37 S. maltophilia isolates not susceptible to levofloxacin and/or TMP-SMZ were determined. Nine strains with various cefiderocol MICs were then tested in time-kill experiments with cefiderocol alone and in combination with comparators. The only agents for which susceptibility rates exceeded 40% were cefiderocol (100%) and minocycline (97.3%). Cefiderocol displayed the lowest MIC50 and MIC90 values (0.125 and 0.5 mg/liter, respectively). In time-kill experiments, synergy was observed when cefiderocol was combined with levofloxacin, minocycline, polymyxin B, or TMP-SMZ against 4/9 (44.4%), 6/9 (66.7%), 5/9 (55.5%), and 6/9 (66.7%) isolates, respectively. These data suggest that cefiderocol displays potent in vitro activity against S. maltophilia, including strains resistant to currently preferred agents. Future dynamic and in vivo studies of cefiderocol alone and in combination are warranted to further define cefiderocol’s synergistic capabilities and its place in therapy for S. maltophilia infections.

scholarly journals In Vitro Activity of Ceftolozane-Tazobactam against Multidrug-Resistant Nonfermenting Gram-Negative Bacilli Isolated from Patients with Cystic Fibrosis

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Patrick Grohs ◽  
Gary Taieb ◽  
Philippe Morand ◽  
Iheb Kaibi ◽  
Isabelle Podglajen ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Stenotrophomonas Maltophilia ◽  
Active Agent ◽  
Multidrug Resistant ◽  
In Vitro Activity ◽  
Gram Negative ◽  
Content Type ◽  
Time Kill

ABSTRACT Ceftolozane-tazobactam was tested against 58 multidrug-resistant nonfermenting Gram-negative bacilli (35 Pseudomonas aeruginosa, 11 Achromobacter xylosoxydans, and 12 Stenotrophomonas maltophilia isolates) isolated from cystic fibrosis patients and was compared to ceftolozane alone, ceftazidime, meropenem, and piperacillin-tazobactam. Ceftolozane-tazobactam was the most active agent against P. aeruginosa but was inactive against A. xylosoxydans and S. maltophilia. In time-kill experiments, ceftolozane-tazobactam had complete bactericidal activity against 2/6 clinical isolates (33%).

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 Vivo Efficacy of Simulated Human Dosing Regimens of Prolonged-Infusion Doripenem against Carbapenemase- Producing Klebsiella pneumoniae

2010 ◽  
Vol 54 (10) ◽  
pp. 4112-4115 ◽  
Author(s):  
Catharine C. Bulik ◽  
David P. Nicolau
Keyword(s):  
Klebsiella Pneumoniae ◽  
White Blood Cells ◽  
Multidrug Resistant ◽  
Gram Negative ◽  
Wide Range ◽  
Dosing Regimens ◽  
Gram Negative Organisms ◽  
Immunocompromised Mice

ABSTRACT Carbapenemase-producing Klebsiella pneumoniae (KPC) bacteria are rapidly becoming one of the most detrimental drug-resistant Gram-negative pathogens. Doripenem is the newest FDA-approved carbapenem that has the greatest in vitro potency against a wide range of Gram-negative organisms, including multidrug-resistant organisms. Previous work in an animal model has shown efficacy against Pseudomonas aeruginosa with MICs above the current breakpoints of susceptibility. The purpose of this study is to evaluate the efficacy of 1-g and 2-g dose prolonged infusions of doripenem against KPC isolates in both an immunocompetent and neutropenic murine thigh model. Seven clinical KPC isolates (broth microdilution [BMD] MIC range, 4 to 32 μg/ml; Etest MIC range, 3 to >32 μg/ml) were used. After infection, groups of mice were administered doripenem doses previously shown to simulate the exposures observed in humans after the administration of 1 or 2 g every 8 h as a 4-h infusion. In immunocompromised mice, 1- and 2-g doses of doripenem achieved bacteriostasis against isolates with MICs up to and including 8 μg/ml and 16 μg/ml, respectively. In immunocompetent animals, statistically significant reductions in the number of CFU were observed with overall decreases of approximately 1 log (P < 0.05). While carbapenemase-producing Klebsiella pneumoniae continues to decrease our meager supply of active agents, the ability of doripenem to produce CFU reductions in the presence of white blood cells (WBCs) using humanized exposures suggests the potential utility of this agent in combination against this increasingly problematic pathogen.

scholarly journals In Vitro and In Vivo Evaluation of the Antifungal Activity of APX001A/APX001 against Candida auris

2018 ◽  
Vol 62 (3) ◽  
pp. e02319-17 ◽  
Author(s):  
Christopher L. Hager ◽  
Emily L. Larkin ◽  
Lisa Long ◽  
Fatima Zohra Abidi ◽  
Karen J. Shaw ◽  
...  
Keyword(s):  
Geographical Area ◽  
Multidrug Resistant ◽  
High Morbidity ◽  
Candida Auris ◽  
In Vivo Evaluation ◽  
Content Type ◽  
Log Reduction ◽  
Invasive Infections

ABSTRACT Candida auris is an emerging multidrug-resistant yeast that has been responsible for invasive infections associated with high morbidity and mortality. C. auris strains often demonstrate high fluconazole and amphotericin B MIC values, and some strains are resistant to all three major antifungal classes. We evaluated the susceptibility of 16 C. auris clinical strains, isolated from a wide geographical area, to 10 antifungal agents, including APX001A, a novel agent that inhibits the fungal protein Gwt1 (glycosylphosphatidylinositol-anchored wall transfer protein 1). APX001A demonstrated significantly lower MIC50 and MIC90 values (0.004 and 0.031 μg/ml, respectively) than all other agents tested. The efficacy of the prodrug APX001 was evaluated in an immunocompromised murine model of disseminated C. auris infection. Significant efficacy (80 to 100% survival) was observed in all three APX001 treatment groups versus 50% survival for the anidulafungin treatment group. In addition, APX001 showed a significant log reduction in CFU counts in kidney, lung, and brain tissue (1.03 to 1.83) versus the vehicle control. Anidulafungin also showed a significant log reduction in CFU in the kidneys and lungs (1.5 and 1.62, respectively) but did not impact brain CFU. These data support further clinical evaluation of this new antifungal agent.

scholarly journals Bactericidal Monoclonal Antibodies Specific to the Lipopolysaccharide O Antigen from Multidrug-Resistant Escherichia coli Clone ST131-O25b:H4 Elicit Protection in Mice

2015 ◽  
Vol 59 (6) ◽  
pp. 3109-3116 ◽  
Author(s):  
Valéria Szijártó ◽  
Luis M. Guachalla ◽  
Zehra C. Visram ◽  
Katharina Hartl ◽  
Cecília Varga ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Monoclonal Antibodies ◽  
Human Serum ◽  
Significant Proportion ◽  
Multidrug Resistant ◽  
Bacterial Killing ◽  
Content Type ◽  
E Coli

ABSTRACTTheEscherichia colisequence type 131 (ST131)-O25b:H4 clone has spread worldwide and become responsible for a significant proportion of multidrug-resistant extraintestinal infections. We generated humanized monoclonal antibodies (MAbs) that target the lipopolysaccharide O25b antigen conserved within this lineage. These MAbs bound to the surface of live bacterial cells irrespective of the capsular type expressed. In a serum bactericidal assayin vitro, MAbs induced >95% bacterial killing in the presence of human serum as the complement source. Protective efficacy at low antibody doses was observed in a murine model of bacteremia. The mode of actionin vivowas investigated by using aglycosylated derivatives of the protective MAbs. The significant binding to liveE. colicells and thein vitroandin vivoefficacy were corroborated in assays using bacteria grown in human serum to mimic relevant clinical conditions. Given the dry pipeline of novel antibiotics against multidrug-resistant Gram-negative pathogens, passive immunization with bactericidal antibodies offers a therapeutic alternative to control infections caused byE. coliST131-O25b:H4.

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