scholarly journals In Vivo Efficacy of Humanized WCK 5222 (Cefepime-Zidebactam) Exposures against Carbapenem-Resistant Acinetobacter baumannii in the Neutropenic Thigh Model

2018 ◽  
Vol 63 (1) ◽  
Author(s):  
Safa S. Almarzoky Abuhussain ◽  
Lindsay M. Avery ◽  
Kamilia Abdelraouf ◽  
David P. Nicolau
Keyword(s):  
Acinetobacter Baumannii ◽  
Infection Model ◽  
Bacterial Burden ◽  
In Vivo Efficacy ◽  
Content Type ◽  
Carbapenem Resistant

ABSTRACT Herein, we describe the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) exposure against carbapenem-resistant Acinetobacter baumannii strains in a neutropenic murine thigh infection model. Five of the six isolates examined expressed OXA-23 or OXA-24. WCK 5222, despite showing MICs of 16 to 64 mg/liter, produced remarkable in vivo activity; human-simulated exposure showed a decline in the bacterial burden for all isolates (mean reduction, −2.09 ± 1.01 log10 CFU/thigh), while a lack of activity was observed with cefepime and zidebactam monotherapies.

scholarly journals Assessment of the In Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) against Carbapenem-Resistant Acinetobacter baumannii in the Neutropenic Murine Lung Infection Model

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Lindsay M. Avery ◽  
Kamilia Abdelraouf ◽  
David P. Nicolau
Keyword(s):  
Acinetobacter Baumannii ◽  
Lung Infection ◽  
Infection Model ◽  
Bacterial Burden ◽  
In Vivo Efficacy ◽  
Content Type ◽  
Murine Lung ◽  
Carbapenem Resistant ◽  
The Mean

ABSTRACT We evaluated the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) against cefepime-resistant Acinetobacter baumannii strains (n = 13) in the neutropenic murine lung infection model. Twelve isolates were meropenem resistant. In control animals and those that received cefepime or zidebactam alone, the mean bacterial growth at 24 h was >2 log10 CFU/lung compared with 0-h controls (6.32 ± 0.33 log10 CFU/lung). WCK 5222 produced a decline in the bacterial burden for all isolates (mean reduction, −3.34 ± 0.85 log10 CFU/lung) and demonstrated remarkable potency.

scholarly journals In Vivo Efficacy of Novel Monobactam LYS228 in Murine Models of Carbapenemase-Producing Klebsiella pneumoniae Infection

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
W. J. Weiss ◽  
M. E. Pulse ◽  
P. Nguyen ◽  
E. J. Growcott
Keyword(s):  
Klebsiella Pneumoniae ◽  
Clinical Development ◽  
Murine Models ◽  
Bacterial Burden ◽  
In Vivo Efficacy ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Infection Models ◽  
Resistant Strains

ABSTRACT LYS228 has potent antibacterial activity against carbapenem-resistant strains of Enterobacteriaceae. LYS228 was efficacious in neutropenic thigh models established with Klebsiella pneumoniae producing KPC-2 or NDM-1; pretreatment with uranyl nitrate considerably shifted calculated static doses of LYS228. In murine ascending pyelonephritis, LYS228 reduced bacterial burden in kidney, urine, and bladder. The successful treatment of murine infection models established with carbapenem-resistant K. pneumoniae further supports the clinical development of LYS228.

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 Semimechanistic Pharmacokinetic/Pharmacodynamic Modeling of Fosfomycin and Sulbactam Combination against Carbapenem-Resistant Acinetobacter baumannii

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Sazlyna Mohd Sazlly Lim ◽  
Aaron J. Heffernan ◽  
Jason A. Roberts ◽  
Fekade B. Sime
Keyword(s):  
Acinetobacter Baumannii ◽  
Treatment Options ◽  
Pharmacodynamic Modeling ◽  
Synergistic Activity ◽  
Bacterial Burden ◽  
Target Attainment ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Time Kill

ABSTRACT Due to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are now considered potential treatments for CR-AB. This study aimed to explore the utility of fosfomycin-sulbactam combination (FOS/SUL) therapy against CR-AB isolates. Synergism of FOS/SUL against 50 clinical CR-AB isolates was screened using the checkerboard method. Thereafter, time-kill studies against two CR-AB isolates were performed. The time-kill data were described using a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Monte Carlo simulations were then performed to estimate the probability of stasis, 1-log kill, and 2-log kill after 24 h of combination therapy. The FOS/SUL combination demonstrated a synergistic effect against 74% of isolates. No antagonism was observed. The MIC50 and MIC90 of FOS/SUL were decreased 4- to 8-fold, compared to the monotherapy MIC50 and MIC90. In the time-kill studies, the combination displayed bactericidal activity against both isolates and synergistic activity against one isolate at the highest clinically achievable concentrations. Our PK/PD model was able to describe the interaction between fosfomycin and sulbactam in vitro. Bacterial kill was mainly driven by sulbactam, with fosfomycin augmentation. FOS/SUL regimens that included sulbactam at 4 g every 8 h demonstrated a probability of target attainment of 1-log10 kill at 24 h of ∼69 to 76%, compared to ∼15 to 30% with monotherapy regimens at the highest doses. The reduction in the MIC values and the achievement of a moderate PTA of a 2-log10 reduction in bacterial burden demonstrated that FOS/SUL may potentially be effective against some CR-AB infections.

scholarly journals Combating Carbapenem-ResistantAcinetobacter baumanniiby an Optimized Imipenem-plus-Tobramycin Dosage Regimen: Prospective Validation via Hollow-Fiber Infection and Mathematical Modeling

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Cornelia B. Landersdorfer ◽  
Rajbharan Yadav ◽  
Kate E. Rogers ◽  
Tae Hwan Kim ◽  
Beom Soo Shin ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Acinetobacter Baumannii ◽  
Hollow Fiber ◽  
Dosage Regimen ◽  
Infection Model ◽  
Bacterial Killing ◽  
Content Type ◽  
Carbapenem Resistant

ABSTRACTWe aimed to prospectively validate an optimized combination dosage regimen against a clinical carbapenem-resistantAcinetobacter baumannii(CRAB) isolate (imipenem MIC, 32 mg/liter; tobramycin MIC, 2 mg/liter). Imipenem at constant concentrations (7.6, 13.4, and 23.3 mg/liter, reflecting a range of clearances) was simulated in a 7-day hollow-fiber infection model (inoculum, ∼107.2CFU/ml) with and without tobramycin (7 mg/kg q24h, 0.5-h infusions). While monotherapies achieved no killing or failed by 24 h, this rationally optimized combination achieved >5 log10bacterial killing and suppressed resistance.

scholarly journals Investigation of Novel pmrB and eptA Mutations in Isogenic Acinetobacter baumannii Isolates Associated with Colistin Resistance and Increased Virulence In Vivo

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Stefanie Gerson ◽  
Jonathan W. Betts ◽  
Kai Lucaßen ◽  
Carolina Silva Nodari ◽  
Julia Wille ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Lipid A ◽  
Galleria Mellonella ◽  
Resistance Mechanism ◽  
Resistant Isolate ◽  
Infection Model ◽  
Colistin Resistance ◽  
Strain Specificity ◽  
Content Type

ABSTRACT Colistin resistance in Acinetobacter baumannii is of great concern and is a threat to human health. In this study, we investigate the mechanisms of colistin resistance in four isogenic pairs of A. baumannii isolates displaying an increase in colistin MICs. A mutation in pmrB was detected in each colistin-resistant isolate, three of which were novel (A28V, I232T, and ΔL9-G12). Increased expression of pmrC was shown by semi-quantitative reverse transcription-PCR (qRT-PCR) for three colistin-resistant isolates, and the addition of phosphoethanolamine (PEtN) to lipid A by PmrC was revealed by mass spectrometry. Interestingly, PEtN addition was also observed in some colistin-susceptible isolates, indicating that this resistance mechanism might be strain specific and that other factors could contribute to colistin resistance. Furthermore, the introduction of pmrAB carrying the short amino acid deletion ΔL9-G12 into a pmrAB knockout strain resulted in increased pmrC expression and lipid A modification, but colistin MICs remained unchanged, further supporting the strain specificity of this colistin resistance mechanism. Of note, a mutation in the pmrC homologue eptA and a point mutation in ISAba1 upstream of eptA were associated with colistin resistance and increased eptA expression, which is a hitherto undescribed resistance mechanism. Moreover, no cost of fitness was observed for colistin-resistant isolates, while the virulence of these isolates was increased in a Galleria mellonella infection model. Although the mutations in pmrB were associated with colistin resistance, PEtN addition appears not to be the sole factor leading to colistin resistance, indicating that the mechanism of colistin resistance is far more complex than previously suspected and is potentially strain specific.

scholarly journals In Vitro and In Vivo Activity of AS101 against Carbapenem-Resistant Acinetobacter baumannii

2021 ◽  
Vol 14 (8) ◽  
pp. 823
Author(s):  
Tsung-Ying Yang ◽  
Sung-Pin Tseng ◽  
Heather Nokulunga Dlamini ◽  
Po-Liang Lu ◽  
Lin Lin ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Antibacterial Activities ◽  
Treated Group ◽  
Infection Model ◽  
High Dose ◽  
Mouse Infection Model ◽  
Carbapenem Resistant ◽  
Time Kill

The increasing trend of carbapenem-resistant Acinetobacter baumannii (CRAB) worldwide has become a concern, limiting therapeutic alternatives and increasing morbidity and mortality rates. The immunomodulation agent ammonium trichloro (dioxoethylene-O,O′-) tellurate (AS101) was repurposed as an antimicrobial agent against CRAB. Between 2016 and 2018, 27 CRAB clinical isolates were collected in Taiwan. The in vitro antibacterial activities of AS101 were evaluated using broth microdilution, time-kill assay, reactive oxygen species (ROS) detection and electron microscopy. In vivo effectiveness was assessed using a sepsis mouse infection model. The MIC range of AS101 for 27 CRAB isolates was from 0.5 to 32 µg/mL, which is below its 50% cytotoxicity (approximately 150 µg/mL). Bactericidal activity was confirmed using a time-kill assay. The antibacterial mechanism of AS101 was the accumulation of the ROS and the disruption of the cell membrane, which, in turn, results in cell death. The carbapenemase-producing A. baumannii mouse sepsis model showed that AS101 was a better therapeutic effect than colistin. The mice survival rate after 120 h was 33% (4/12) in the colistin-treated group and 58% (7/12) in the high-dose AS101 (3.33 mg/kg/day) group. Furthermore, high-dose AS101 significantly decreased bacterial population in the liver, kidney and spleen (all p < 0.001). These findings support the concept that AS101 is an ideal candidate for further testing in future studies.

scholarly journals Assessment of the In Vivo Activity of SPR741 in Combination with Azithromycin against Multidrug-Resistant Enterobacteriaceae Isolates in the Neutropenic Murine Thigh Infection Model

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Sean M. Stainton ◽  
Kamilia Abdelraouf ◽  
Luke Utley ◽  
Michael J. Pucci ◽  
Troy Lister ◽  
...  
Keyword(s):  
Potential Role ◽  
Wide Spectrum ◽  
Structural Similarity ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Bacterial Burden ◽  
Content Type ◽  
Novel Agent

ABSTRACT SPR741 is a novel agent with structural similarity to polymyxins that is capable of potentiating the activities of various classes of antibiotics. Previously published studies indicated that although Enterobacteriaceae isolates had minimal susceptibilities to azithromycin (AZM), the in vitro antimicrobial activity of AZM against Enterobacteriaceae was enhanced when it was combined with SPR741. The current study evaluated the in vivo activity of human-simulated regimens (HSR) of AZM equivalent to clinical doses of 500 mg given intravenously (i.v.) every 24 h (q24h) and SPR741 equivalent to clinical doses of 400 mg q8h i.v. (1-h infusion), alone and in combination, against multidrug-resistant (MDR) Enterobacteriaceae . We studied 30 MDR Enterobacteriaceae isolates expressing a wide spectrum of β-lactamases (ESBL, NDM, VIM, and KPC), including a subset of isolates positive for genes conferring macrolide resistance ( mphA , mphE , ermB , and msr ). In vivo activity was assessed as the change in log 10 CFU per thigh at 24 h compared with 0 h. Treatment with AZM alone was associated with net growth of 2.60 ± 0.83 log 10 CFU/thigh. Among isolates with AZM MICs of ≤16 mg/liter, treatment with AZM-SPR741was associated with an average reduction in bacterial burden of −0.53 ± 0.82 log 10 CFU/thigh, and stasis to 1-log kill was observed in 9/11 isolates (81.8%). Combination therapy with an AZM-SPR741 HSR showed promising in vivo activity against MDR Enterobacteriaceae isolates with AZM MICs of ≤16 mg/liter, including those producing a variety of β-lactamases. These data support a potential role for AZM-SPR741 in the treatment of infections due to MDR Enterobacteriaceae .

scholarly journals In VivoApplication of Bacteriophage as a Potential Therapeutic Agent To Control OXA-66-Like Carbapenemase-Producing Acinetobacter baumannii Strains Belonging to Sequence Type 357

2016 ◽  
Vol 82 (14) ◽  
pp. 4200-4208 ◽  
Author(s):  
Jongsoo Jeon ◽  
Choong-Min Ryu ◽  
Jun-Young Lee ◽  
Jong-Hwan Park ◽  
Dongeun Yong ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
In Silico ◽  
Therapeutic Agent ◽  
Clinical Isolates ◽  
Infection Model ◽  
Bacterial Challenge ◽  
Content Type ◽  
Lysis Activity

ABSTRACTThe increasing prevalence of carbapenem-resistantAcinetobacter baumannii(CRAB) strains in intensive care units has caused major problems in public health worldwide. Our aim was to determine whether this phage could be used as an alternative therapeutic agent against multidrug-resistant bacterial strains, specifically CRAB clinical isolates, using a mouse model. Ten bacteriophages that caused lysis in CRAB strains, includingblaOXA-66-likegenes, were isolated. YMC13/01/C62 ABA BP (phage Bϕ-C62), which showed the strongest lysis activity, was chosen for further study by transmission electron microscopy (TEM), host range test, one-step growth and phage adsorption rate, thermal and pH stability, bacteriolytic activity test, genome sequencing and bioinformatics analysis, and therapeutic effect of phage using a mouse intranasal infection model. The phage Bϕ-C62 displayed high stability at various temperatures and pH values and strong cell lysis activityin vitro. The phage Bϕ-C62 genome has a double-stranded linear DNA with a length of 44,844 bp, and known virulence genes were not identifiedin silico. In vivostudy showed that all mice treated with phage Bϕ-C62 survived after intranasal bacterial challenge. Bacterial clearance in the lung was observed within 3 days after bacterial challenge, and histologic damage also improved significantly; moreover, no side effects were observed.IMPORTANCEIn our study, the novelA. baumanniiphage Bϕ-C62 was characterized and evaluatedin vitro,in silico, andin vivo. These results, including strong lytic activities and the improvement of survival rates, showed the therapeutic potential of the phage Bϕ-C62 as an antimicrobial agent. This study reports the potential of a novel phage as a therapeutic candidate or nontoxic disinfectant against CRAB clinical isolatesin vitroandin vivo.

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