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 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 VivoPharmacodynamic Study of Cefiderocol, a Novel Parenteral Siderophore Cephalosporin, in Murine Thigh and Lung Infection Models

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Rio Nakamura ◽  
Tsukasa Ito-Horiyama ◽  
Miki Takemura ◽  
Shinsuke Toba ◽  
Shuhei Matsumoto ◽  
...  
Keyword(s):  
Lung Infection ◽  
Infection Model ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Mueller Hinton ◽  
Infection Models ◽  
Resistant Strains ◽  
The Mean ◽  
Mueller Hinton Broth

ABSTRACTThe pharmacokinetic (PK) and pharmacodynamic (PD) parameters which correlated with thein vivoefficacy of cefiderocol were evaluated using neutropenic murine thigh and lung infection models in which the infections were caused by a variety of Gram-negative bacilli. The dose fractionation study using the thigh infection model in which the infection was caused byPseudomonas aeruginosashowed that the cumulative percentage of a 24-h period that the free drug concentration in plasma exceeds the MIC (%fT>MIC) rather than the free peak level divided by the MIC (fCmax/MIC) and the area under the free concentration-time curve over 24 h divided by the MIC (fAUC/MIC) was the PK/PD parameter that best correlated with efficacy. The study with multiple carbapenem-resistant strains revealed that the %fT>MICdetermined in iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) better reflected thein vivoefficacy of cefiderocol than the %fT>MICdetermined in cation-adjusted Mueller-Hinton broth (CAMHB). The mean %fT>MICof cefiderocol required for a 1-log10reduction against 10 strains ofEnterobacteriaceaeand 3 strains ofPseudomonas aeruginosain the thigh infection models were 73.3% and 77.2%, respectively. The mean %fT>MICforEnterobacteriaceae,P. aeruginosa,Acinetobacter baumannii, andStenotrophomonas maltophiliain the lung infection model were 64.4%, 70.3%, 88.1%, and 53.9%, respectively. These results indicate that cefiderocol has potent efficacy against Gram-negative bacilli, including carbapenem-resistant strains, irrespective of the bacterial species, in neutropenic thigh and lung infection models and that thein vivoefficacy correlated with thein vitroMIC under iron-deficient conditions.

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 Fighting Antibiotic-Resistant Klebsiella pneumoniae with “Sweet” Immune Targets

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Roberto Adamo ◽  
Immaculada Margarit
Keyword(s):  
Klebsiella Pneumoniae ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Therapeutic Approaches ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Surface Polysaccharides ◽  
Resistant Strains ◽  
Murine Monoclonal Antibodies

ABSTRACT Antibiotics and vaccines have greatly impacted human health in the last century by dramatically reducing the morbidity and mortality associated with infectious diseases. The recent challenge posed by the emergence of multidrug-resistant bacteria could possibly be addressed by novel immune prophylactic and therapeutic approaches. Among the newly threatening pathogens, Klebsiella pneumoniae is particularly worrisome in the nosocomial setting, and its surface polysaccharides are regarded as promising antigen candidates. The majority of Klebsiella carbapenem-resistant strains belong to the sequence type 158 (ST258) lineage, with two main clades expressing capsular polysaccharides CPS1 and CPS2. In a recent article, S. D. Kobayashi and colleagues (mBio 9:e00297-18, 2018, https://doi.org/10.1128/mBio.00297-18) show that CPS2-specific IgGs render ST258 clade 2 bacteria more sensitive to human serum and phagocytic killing. E. Diago-Navarro et al. (mBio 9:e00091-18, 2018, https://doi.org/10.1128/mBio.00091-18) generated two murine monoclonal antibodies recognizing distinct glycotopes of CPS2 that presented functional activity against multiple ST258 strains. These complementary studies represent a step toward the control of this dangerous pathogen.

scholarly journals Serum Antibody Responses against Carbapenem-Resistant Klebsiella pneumoniae in Infected Patients

mSphere ◽  
2021 ◽  
Vol 6 (2) ◽  
Author(s):  
Kasturi Banerjee ◽  
Michael P. Motley ◽  
Elizabeth Diago-Navarro ◽  
Bettina C. Fries
Keyword(s):  
Klebsiella Pneumoniae ◽  
Capsular Polysaccharide ◽  
Serum Antibody ◽  
Antibody Responses ◽  
Capsular Polysaccharides ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Reactive Properties

ABSTRACT Capsular polysaccharide (CPS) heterogeneity within carbapenem-resistant Klebsiella pneumoniae (CR-Kp) strain sequence type 258 (ST258) must be considered when developing CPS-based vaccines. Here, we sought to characterize CPS-specific antibody responses elicited by CR-Kp-infected patients. Plasma and bacterial isolates were collected from 33 hospital patients with positive CR-Kp cultures. Isolate capsules were typed by wzi sequencing. Reactivity and measures of efficacy of patient antibodies were studied against 3 prevalent CR-Kp CPS types (wzi29, wzi154, and wzi50). High IgG titers against wzi154 and wzi50 CPS were documented in 79% of infected patients. Patient-derived (PD) IgGs agglutinated CR-Kp and limited growth better than naive IgG and promoted phagocytosis of strains across the serotype isolated from their donors. Additionally, poly-IgG from wzi50 and wzi154 patients promoted phagocytosis of nonconcordant CR-Kp serotypes. Such effects were lost when poly-IgG was depleted of CPS-specific IgG. Additionally, mice infected with wzi50, wzi154, and wzi29 CR-Kp strains preopsonized with wzi50 patient-derived IgG exhibited lower lung CFU than controls. Depletion of wzi50 antibodies (Abs) reversed this effect in wzi50 and wzi154 infections, whereas wzi154 Ab depletion reduced poly-IgG efficacy against wzi29 CR-Kp. We are the first to report cross-reactive properties of CPS-specific Abs from CR-Kp patients through both in vitro and in vivo models. IMPORTANCE Carbapenem-resistant Klebsiella pneumoniae is a rapidly emerging public health threat that can cause fatal infections in up to 50% of affected patients. Due to its resistance to nearly all antimicrobials, development of alternate therapies like antibodies and vaccines is urgently needed. Capsular polysaccharides constitute important targets, as they are crucial for Klebsiella pneumoniae pathogenesis. Capsular polysaccharides are very diverse and, therefore, studying the host’s capsule-type specific antibodies is crucial to develop effective anti-CPS immunotherapies. In this study, we are the first to characterize humoral responses in infected patients against carbapenem-resistant Klebsiella pneumoniae expressing different wzi capsule types. This study is the first to report the efficacy of cross-reactive properties of CPS-specific Abs in both in vitro and in vivo models.

scholarly journals In Vivo Efficacy of Cefiderocol against Carbapenem-Resistant Gram-Negative Bacilli in Murine Urinary Tract Infection Models

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S472-S472 ◽  
Author(s):  
Shuhei Matsumoto ◽  
Sachi Kanazawa ◽  
Rio Nakamura ◽  
Masakatsu Tsuji ◽  
Takafumi Sato ◽  
...  
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
In Vivo Efficacy ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Infection Models

scholarly journals Genome-Wide Screening for Enteric Colonization Factors in Carbapenem-Resistant ST258 Klebsiella pneumoniae

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Hea-Jin Jung ◽  
Eric R. Littmann ◽  
Ruth Seok ◽  
Ingrid M. Leiner ◽  
Ying Taur ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Genetic Factors ◽  
Intestinal Lumen ◽  
Intestinal Colonization ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Gut Colonization ◽  
Colonization Factors

ABSTRACT A diverse, antibiotic-naive microbiota prevents highly antibiotic-resistant microbes, including carbapenem-resistant Klebsiella pneumoniae (CR-Kp), from achieving dense colonization of the intestinal lumen. Antibiotic-mediated destruction of the microbiota leads to expansion of CR-Kp in the gut, markedly increasing the risk of bacteremia in vulnerable patients. While preventing dense colonization represents a rational approach to reduce intra- and interpatient dissemination of CR-Kp, little is known about pathogen-associated factors that enable dense growth and persistence in the intestinal lumen. To identify genetic factors essential for dense colonization of the gut by CR-Kp, we constructed a highly saturated transposon mutant library with >150,000 unique mutations in an ST258 strain of CR-Kp and screened for in vitro growth and in vivo intestinal colonization in antibiotic-treated mice. Stochastic and partially reversible fluctuations in the representation of different mutations during dense colonization revealed the dynamic nature of intestinal microbial populations. We identified genes that are crucial for early and late stages of dense gut colonization and confirmed their role by testing isogenic mutants in in vivo competition assays with wild-type CR-Kp. Screening of the transposon library also identified mutations that enhanced in vivo CR-Kp growth. These newly identified colonization factors may provide novel therapeutic opportunities to reduce intestinal colonization by CR-Kp. IMPORTANCE Klebsiella pneumoniae is a common cause of bloodstream infections in immunocompromised and hospitalized patients, and over the last 2 decades, some strains have acquired resistance to nearly all available antibiotics, including broad-spectrum carbapenems. The U.S. Centers for Disease Control and Prevention has listed carbapenem-resistant K. pneumoniae (CR-Kp) as an urgent public health threat. Dense colonization of the intestine by CR-Kp and other antibiotic-resistant bacteria is associated with an increased risk of bacteremia. Reducing the density of gut colonization by CR-Kp is likely to reduce their transmission from patient to patient in health care facilities as well as systemic infections. How CR-Kp expands and persists in the gut lumen, however, is poorly understood. Herein, we generated a highly saturated mutant library in a multidrug-resistant K. pneumoniae strain and identified genetic factors that are associated with dense gut colonization by K. pneumoniae. This study sheds light on host colonization by K. pneumoniae and identifies potential colonization factors that contribute to high-density persistence of K. pneumoniae in the intestine.

scholarly journals In VivoEfficacy of Humanized Exposures of Ceftazidime-Avibactam in Comparison with Ceftazidime against Contemporary Enterobacteriaceae Isolates

2014 ◽  
Vol 58 (11) ◽  
pp. 6913-6919 ◽  
Author(s):  
Shawn H. MacVane ◽  
Jared L. Crandon ◽  
Wright W. Nichols ◽  
David P. Nicolau
Keyword(s):  
Gram Negative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class D ◽  
Variable Activity ◽  
Resistant Strains ◽  
The Impact ◽  
Inhibitor Combination ◽  
Lactamase Inhibitor

ABSTRACTCeftazidime-avibactam is a β-lactam β-lactamase inhibitor combination under investigation for the treatment of serious Gram-negative infections. When combined with avibactam, a novel non-β-lactam β-lactamase inhibitor, ceftazidime has activity against isolates that produce Ambler class A, class C, and some class D β-lactamases. However, little is known of thein vivoefficacy of the combination against these targeted ceftazidime- and carbapenem-resistantEnterobacteriaceae. Using humanized exposures in the murine thigh model, we evaluated the efficacy of ceftazidime-avibactam againstEnterobacteriaceaeexhibiting MICs of ≥8 μg/ml to aid in the assignment of interpretive susceptibility criteria. Eighteen clinicalEnterobacteriaceaeisolates, including nine carbapenem-resistant strains, were evaluated against ceftazidime-avibactam (2,000 mg/500 mg) as a 2-h infusion every 8 h. To highlight the impact of avibactam, 13 select isolates were tested in the neutropenic model against a humanized regimen of 2,000 mg ceftazidime every 8 h (2-h infusion). Additionally, nine isolates were evaluated in immunocompetent animals. The efficacy was evaluated as the change in log10CFU compared with that of 0-h controls after 24 h. The vast majority (17/18, 94%) of the isolates were resistant to ceftazidime alone. The ceftazidime monotherapy failed to have activity against 10 of 13 isolates, while ceftazidime-avibactam produced reductions in bacterial density against 16 of 18 isolates. Ceftazidime-avibactam (2,000 mg/500 mg) every 8 h (2-h infusion) displayed dependable activity against theEnterobacteriaceaeisolates, exhibiting MICs of ≤16 μg/ml (free drug concentration above the MIC [fT>MIC] of ≥62%) and variable activity was noted at an MIC of 32 μg/ml (fT>MICof 34%). The presence of a functioning immune system enhanced the efficacy for both regimens against all tested isolates. These data support further examination of the use of ceftazidime-avibactam as an effective therapy against infections due to Gram-negative infections, including carbapenem-resistantEnterobacteriaceae.

scholarly journals MCR-1 and OXA-48 In Vivo Acquisition in KPC-Producing Escherichia coli after Colistin Treatment

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Racha Beyrouthy ◽  
Frederic Robin ◽  
Aude Lessene ◽  
Igor Lacombat ◽  
Laurent Dortet ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Content Type ◽  
First Report ◽  
E Coli ◽  
Carbapenem Resistant

ABSTRACT The spread of mcr-1-encoding plasmids into carbapenem-resistant Enterobacteriaceae raises concerns about the emergence of untreatable bacteria. We report the acquisition of mcr-1 in a carbapenem-resistant Escherichia coli strain after a 3-week course of colistin in a patient repatriated to France from Portugal. Whole-genome sequencing revealed that the Klebsiella pneumoniae carbapenemase-producing E. coli strain acquired two plasmids, an IncL OXA-48-encoding plasmid and an IncX4 mcr-1-encoding plasmid. This is the first report of mcr-1 in carbapenemase-encoding bacteria in France.

scholarly journals Control of Klebsiella pneumoniae Infection in Mice by Using Dissolving Microarray Patches Containing Gentamicin

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Aoife M. Rodgers ◽  
Maelíosa T. C. McCrudden ◽  
Aaron J. Courtenay ◽  
Mary-Carmel Kearney ◽  
Katherine L. Edwards ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Bacterial Infection ◽  
Murine Model ◽  
Lymphoid Tissue ◽  
Published Data ◽  
Proof Of Concept ◽  
Bacterial Burden ◽  
Content Type ◽  
Concept Study

ABSTRACT Using a murine model of Klebsiella pneumoniae bacterial infection, we demonstrate that gentamicin dissolving microarray patches, applied to murine ears, could control K. pneumoniae infection. Mice treated with microarray patches had reduced bacterial burden in the nasal-associated lymphoid tissue and lungs compared with their untreated counterparts. This proof of concept study represents the first published data on the in vivo delivery of the antibiotic gentamicin via dissolving microarray patches, resulting in the control of bacterial infection.

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