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 Paenipeptin Analogues Potentiate Clarithromycin and Rifampin against mcr-1-Mediated Polymyxin-Resistant Escherichia coli In Vivo

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Sun Hee Moon ◽  
Yihong Kaufmann ◽  
En Huang
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Resistance ◽  
Outer Membrane ◽  
Infection Model ◽  
Gram Negative ◽  
Content Type ◽  
E Coli ◽  
Log Reduction

ABSTRACT Polymyxin resistance mediated by the mcr-1 gene threatens the last-resort antibiotics. Linear lipopeptide paenipeptin analogues 1 and 15 disrupted the outer membrane of Gram-negative pathogens and potentiated clarithromycin and rifampin against mcr-1-positive Escherichia coli from the FDA-CDC Antimicrobial Resistance Isolate Bank. In the presence of paenipeptin, clarithromycin and rifampin resulted in over 3-log reduction of E. coli in vitro. Moreover, paenipeptin-antibiotic combinations significantly reduced E. coli in a murine thigh infection model.

scholarly journals Efficacy of Humanized Cefiderocol Exposures over 72 Hours against a Diverse Group of Gram-Negative Isolates in the Neutropenic Murine Thigh Infection Model

2018 ◽  
Vol 63 (2) ◽  
pp. e01040-18 ◽  
Author(s):  
Sean M. Stainton ◽  
Marguerite L. Monogue ◽  
Masakatsu Tsuji ◽  
Yoshinori Yamano ◽  
Roger Echols ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Infection Model ◽  
Diverse Group ◽  
Gram Negative ◽  
Content Type ◽  
Adaptive Resistance

ABSTRACT Herein, we evaluated sustainability of humanized exposures of cefiderocol in vivo over 72 h against pathogens with cefiderocol MICs of 0.5 to 16 μg/ml in the neutropenic murine thigh model. In Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae displaying MICs of 0.5 to 8 μg/ml (n = 11), sustained kill was observed at 72 h among 9 isolates. Postexposure MICs revealed a single 2-dilution increase in one animal compared with controls (1/54 samples, 1.8%) at 72 h. Adaptive resistance during therapy was not observed.

scholarly journals Two Functional Type VI Secretion Systems in Avian Pathogenic Escherichia coli Are Involved in Different Pathogenic Pathways

2014 ◽  
Vol 82 (9) ◽  
pp. 3867-3879 ◽  
Author(s):  
Jiale Ma ◽  
Yinli Bao ◽  
Min Sun ◽  
Wenyang Dong ◽  
Zihao Pan ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Chicken Embryo Fibroblast ◽  
Microvascular Endothelial Cell ◽  
Infection Model ◽  
Tail Fiber ◽  
Secretion Systems ◽  
Content Type ◽  
Type Vi Secretion

ABSTRACTType VI secretion systems (T6SSs) are involved in the pathogenicity of several Gram-negative bacteria. The VgrG protein, a core component and effector of T6SS, has been demonstrated to perform diverse functions. The N-terminal domain of VgrG protein is a homologue of tail fiber protein gp27 of phage T4, which performs a receptor binding function and determines the host specificity. Based on sequence analysis, we found that two putative T6SS loci exist in the genome of the avian pathogenicEscherichia coli(APEC) strain TW-XM. To assess the contribution of these two T6SSs to TW-XM pathogenesis, the crucialclpVclusters of these two T6SS loci and theirvgrGgenes were deleted to generate a series of mutants. Consequently, T6SS1-associated mutants presented diminished adherence to and invasion of several host cell lines culturedin vitro, decreased pathogenicity in duck and mouse infection modelsin vivo, and decreased biofilm formation and bacterial competitive advantage. In contrast, T6SS2-associated mutants presented a significant decrease only in the adherence to and invasion of mouse brain microvascular endothelial cell (BMEC) line bEnd.3 and brain tissue of the duck infection model. These results suggested that T6SS1 was involved in the proliferation of APEC in systemic infection, whereas VgrG-T6SS2 was responsible only for cerebral infection. Further study demonstrated that VgrG-T6SS2 was able to bind to the surface of bEnd.3 cells, whereas it did not bind to DF-1 (chicken embryo fibroblast) cells, which further proved the interaction of VgrG-T6SS2 with the surface of BMECs.

scholarly journals In VitroandIn VivoActivities of OP0595, a New Diazabicyclooctane, against CTX-M-15-Positive Escherichia coli and KPC-Positive Klebsiella pneumoniae

2016 ◽  
Vol 60 (5) ◽  
pp. 3001-3006 ◽  
Author(s):  
Akihiro Morinaka ◽  
Yuko Tsutsumi ◽  
Keiko Yamada ◽  
Yoshihiro Takayama ◽  
Shiro Sakakibara ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Infection Model ◽  
Gram Negative Bacteria ◽  
Content Type ◽  
Effective Combination ◽  
Time Kill ◽  
Lactamase Inhibitor

ABSTRACTGram-negative bacteria are evolving to produce β-lactamases of increasing diversity that challenge antimicrobial chemotherapy. OP0595 is a new diazabicyclooctane serine β-lactamase inhibitor which acts also as an antibiotic and as a β-lactamase-independent β-lactam “enhancer” againstEnterobacteriaceae. Here we determined the optimal concentration of OP0595 in combination with piperacillin, cefepime, and meropenem, in addition to the antibacterial activity of OP0595 alone and in combination with cefepime, inin vitrotime-kill studies and anin vivoinfection model against five strains of CTX-M-15-positiveEscherichia coliand five strains of KPC-positiveKlebsiella pneumoniae. An OP0595 concentration of 4 μg/ml was found to be sufficient for an effective combination with all three β-lactam agents. In bothin vitrotime-kill studies and anin vivomodel of infection, cefepime-OP0595 showed stronger efficacy than cefepime alone against all β-lactamase-positive strains tested, whereas OP0595 alone showed weaker or no efficacy. Taken together, these data indicate that combinational use of OP0595 and a β-lactam agent is important to exert the antimicrobial functions of OP0595.

scholarly journals Activities of Fosfomycin, Tigecycline, Colistin, and Gentamicin against Extended-Spectrum-β-Lactamase-Producing Escherichia coli in a Foreign-Body Infection Model

2013 ◽  
Vol 57 (3) ◽  
pp. 1421-1427 ◽  
Author(s):  
Stéphane Corvec ◽  
Ulrika Furustrand Tafin ◽  
Bertrand Betrisey ◽  
Olivier Borens ◽  
Andrej Trampuz
Keyword(s):  
Escherichia Coli ◽  
Foreign Body ◽  
Single Agent ◽  
Infection Model ◽  
Minimal Bactericidal Concentration ◽  
Synergistic Activity ◽  
Cure Rate ◽  
Gram Negative ◽  
Content Type

ABSTRACTLimited antimicrobial agents are available for the treatment of implant-associated infections caused by fluoroquinolone-resistant Gram-negative bacilli. We compared the activities of fosfomycin, tigecycline, colistin, and gentamicin (alone and in combination) against a CTX-M15-producing strain ofEscherichia coli(Bj HDE-1)in vitroand in a foreign-body infection model. The MIC and the minimal bactericidal concentration in logarithmic phase (MBClog) and stationary phase (MBCstat) were 0.12, 0.12, and 8 μg/ml for fosfomycin, 0.25, 32, and 32 μg/ml for tigecycline, 0.25, 0.5, and 2 μg/ml for colistin, and 2, 8, and 16 μg/ml for gentamicin, respectively. In time-kill studies, colistin showed concentration-dependent activity, but regrowth occurred after 24 h. Fosfomycin demonstrated rapid bactericidal activity at the MIC, and no regrowth occurred. Synergistic activity between fosfomycin and colistinin vitrowas observed, with no detectable bacterial counts after 6 h. In animal studies, fosfomycin reduced planktonic counts by 4 log10CFU/ml, whereas in combination with colistin, tigecycline, or gentamicin, it reduced counts by >6 log10CFU/ml. Fosfomycin was the only single agent which was able to eradicateE. colibiofilms (cure rate, 17% of implanted, infected cages). In combination, colistin plus tigecycline (50%) and fosfomycin plus gentamicin (42%) cured significantly more infected cages than colistin plus gentamicin (33%) or fosfomycin plus tigecycline (25%) (P< 0.05). The combination of fosfomycin plus colistin showed the highest cure rate (67%), which was significantly better than that of fosfomycin alone (P< 0.05). In conclusion, the combination of fosfomycin plus colistin is a promising treatment option for implant-associated infections caused by fluoroquinolone-resistant Gram-negative bacilli.

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 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 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 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 Candida albicans and Pseudomonas aeruginosa Interact To Enhance Virulence of Mucosal Infection in Transparent Zebrafish

2017 ◽  
Vol 85 (11) ◽  
Author(s):  
Audrey C. Bergeron ◽  
Brittany G. Seman ◽  
John H. Hammond ◽  
Linda S. Archambault ◽  
Deborah A. Hogan ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Candida Albicans ◽  
The Body ◽  
Host Responses ◽  
Patient Treatment ◽  
Infection Model ◽  
Content Type ◽  
Epithelial Invasion

ABSTRACT Polymicrobial infections often include both fungi and bacteria and can complicate patient treatment and resolution of infection. Cross-kingdom interactions among bacteria, fungi, and/or the immune system during infection can enhance or block virulence mechanisms and influence disease progression. The fungus Candida albicans and the bacterium Pseudomonas aeruginosa are coisolated in the context of polymicrobial infection at a variety of sites throughout the body, including mucosal tissues such as the lung. In vitro, C. albicans and P. aeruginosa have a bidirectional and largely antagonistic relationship. Their interactions in vivo remain poorly understood, specifically regarding host responses in mediating infection. In this study, we examine trikingdom interactions using a transparent juvenile zebrafish to model mucosal lung infection and show that C. albicans and P. aeruginosa are synergistically virulent. We find that high C. albicans burden, fungal epithelial invasion, swimbladder edema, and epithelial extrusion events serve as predictive factors for mortality in our infection model. Longitudinal analyses of fungal, bacterial, and immune dynamics during coinfection suggest that enhanced morbidity is associated with exacerbated C. albicans pathogenesis and elevated inflammation. The P. aeruginosa quorum-sensing-deficient ΔlasR mutant also enhances C. albicans pathogenicity in coinfection and induces extrusion of the swimbladder. Together, these observations suggest that C. albicans-P. aeruginosa cross talk in vivo can benefit both organisms to the detriment of the host.

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