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.

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 SPR741, an Antibiotic Adjuvant, Potentiates the In Vitro and In Vivo Activity of Rifampin against Clinically Relevant Extensively Drug-Resistant Acinetobacter baumannii

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Daniel V. Zurawski ◽  
Alexandria A. Reinhart ◽  
Yonas A. Alamneh ◽  
Michael J. Pucci ◽  
Yuanzheng Si ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Ventilator Associated Pneumonia ◽  
Drug Resistant ◽  
Proof Of Concept ◽  
Bacterial Burden ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Animal Survival

ABSTRACT Acinetobacter baumannii is responsible for 10% of all nosocomial infections and has >50% mortality rates when causing ventilator-associated pneumonia. In this proof-of-concept study, we evaluated SPR741, an antibiotic adjuvant that permeabilizes the Gram-negative membrane, in combination with rifampin against AB5075, an extensively drug-resistant (XDR) A. baumannii strain. In standard in vitro assays and in a murine pulmonary model, we found that this drug combination can significantly reduce bacterial burden and promote animal survival despite an aggressive infection.

scholarly journals Doripenem MICs andompK36Porin Genotypes of Sequence Type 258, KPC-Producing Klebsiella pneumoniae May Predict Responses to Carbapenem-Colistin Combination Therapy among Patients with Bacteremia

2014 ◽  
Vol 59 (3) ◽  
pp. 1797-1801 ◽  
Author(s):  
Ryan K. Shields ◽  
M. Hong Nguyen ◽  
Brian A. Potoski ◽  
Ellen G. Press ◽  
Liang Chen ◽  
...  
Keyword(s):  
Amino Acids ◽  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Sequence Type ◽  
Content Type

ABSTRACTTreatment failures of a carbapenem-colistin regimen among patients with bacteremia due to sequence type 258 (ST258), KPC-2-producingKlebsiella pneumoniaewere significantly more likely if both agents were inactivein vitro, as defined by a colistin MIC of >2 μg/ml and the presence of either a majorompK36porin mutation (guanine and alanine insertions at amino acids 134 and 135 [ins aa 134–135 GD], IS5promoter insertion [P= 0.007]) or a doripenem MIC of >8 μg/ml (P= 0.01). MajorompK36mutations among KPC-K. pneumoniaestrains are important determinants of carbapenem-colistin responsesin vitroandin vivo.

scholarly journals In vivo assessment of neuroinflammation in progressive multiple sclerosis: a proof of concept study with [18F]DPA714 PET

2018 ◽  
Vol 15 (1) ◽  
Author(s):  
Marloes H. J. Hagens ◽  
Sandeep V. Golla ◽  
Martijn T. Wijburg ◽  
Maqsood Yaqub ◽  
Dennis Heijtel ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Progressive Multiple Sclerosis ◽  
Proof Of Concept ◽  
Concept Study ◽  
In Vivo Assessment

scholarly journals Pharmacokinetic and Pharmacodynamic Evaluation of P-873 versus Klebsiella pneumoniae in a Neutropenic Murine Thigh Infection Model

2013 ◽  
Vol 57 (4) ◽  
pp. 1971-1973 ◽  
Author(s):  
Lucinda M. Lamb ◽  
Jared L. Crandon ◽  
David P. Nicolau
Keyword(s):  
Protein Synthesis ◽  
Klebsiella Pneumoniae ◽  
Infection Model ◽  
Protein Synthesis Inhibitors ◽  
Content Type ◽  
Pharmacokinetic Properties

ABSTRACTP-873 is a novel compound in the RX-04 pyrrolocytosine series of protein synthesis inhibitors currently under development by Rib-X Pharmaceuticals. We evaluated the pharmacodynamic and pharmacokinetic properties of this compound againstKlebsiella pneumoniaeusing a murine neutropenic thigh infection model. P-873 demonstrated potent and rapidin vivoactivity against this organism with enhanced penetration and duration of exposure in thigh tissue.

scholarly journals In Vivo Pharmacodynamic Characterization of a Novel Odilorhabdin Antibiotic, NOSO-502, against Escherichia coli and Klebsiella pneumoniae in a Murine Thigh Infection Model

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Miao Zhao ◽  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
Jamie VanHecker ◽  
David R. Andes
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Subcutaneous Administration ◽  
Dose Fractionation ◽  
Infection Model ◽  
Pharmacokinetic Studies ◽  
Time Curve ◽  
Content Type ◽  
The Mean

ABSTRACT NOSO-502 is a novel odilorhabdin antibiotic with potent activity against Enterobacteriaceae. The goal of these studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitude best correlated with efficacy in the murine thigh infection model. Six Escherichia coli and 6 Klebsiella pneumoniae isolates were utilized. MICs were determined using CLSI methods and ranged from 1 to 4 mg/liter. A neutropenic murine thigh infection model was utilized for all treatment studies. Single-dose plasma pharmacokinetics were determined in mice after subcutaneous administration of 7.81, 31.25, 125, and 500 mg/kg of body weight. Pharmacokinetic studies exhibited peak concentration (Cmax) values of 1.49 to 84.6 mg/liter, area under the concentration-time curve from 0 h to infinity (AUC0–∞) values of 1.94 to 352 mg · h/liter, and beta elimination half-lives of 0.41 to 1.1 h. Dose fractionation studies were performed using total drug doses of 7.81 mg/kg to 2,000 mg/kg fractionated into regimens of every 3 h (q3h), q6h, q12h, or q24h. Nonlinear regression analysis demonstrated that AUC/MIC was the PK/PD parameter that best correlated with efficacy (R2, 0.86). In subsequent studies, we used the neutropenic murine thigh infection model to determine the magnitude of NOSO-502 AUC/MIC needed for the efficacy against a diverse group of Enterobacteriaceae. Mice were treated with 4-fold-increasing doses (range, 3.91 to 1,000 mg/kg) of NOSO-502 every 6 h. The mean 24-h free-drug AUC/MIC (fAUC)/MIC) magnitudes associated with net stasis and 1-log kill endpoint for K. pneumoniae were 4.22 and 17.7, respectively. The mean fAUC/MIC magnitude associated with net stasis endpoint for E. coli was 10.4. NOSO-502 represents a promising novel, first-in-class odilorhabdin antibiotic with in vivo potency against Enterobacteriaceae.

Leadless cardiac resynchronization therapy: An in vivo proof-of-concept study of wireless pacemaker synchronization

Heart Rhythm ◽  
2019 ◽  
Vol 16 (6) ◽  
pp. 936-942 ◽  
Author(s):  
Lukas Bereuter ◽  
Thomas Niederhauser ◽  
Martin Kucera ◽  
Dominic Loosli ◽  
Immanuel Steib ◽  
...  
Keyword(s):  
Cardiac Resynchronization Therapy ◽  
Cardiac Resynchronization ◽  
Proof Of Concept ◽  
Resynchronization Therapy ◽  
Concept Study

scholarly journals Experimental Evolution In Vivo To Identify Selective Pressures during Pneumococcal Colonization

mSystems ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Vaughn S. Cooper ◽  
Erin Honsa ◽  
Hannah Rowe ◽  
Christopher Deitrick ◽  
Amy R. Iverson ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Murine Model ◽  
Experimental Evolution ◽  
Nasal Colonization ◽  
Content Type ◽  
Selective Pressures ◽  
Specific Tissue ◽  
Tissue Tropisms ◽  
Insight Into

ABSTRACT Experimental evolution is a powerful technique to understand how populations evolve from selective pressures imparted by the surrounding environment. With the advancement of whole-population genomic sequencing, it is possible to identify and track multiple contending genotypes associated with adaptations to specific selective pressures. This approach has been used repeatedly with model species in vitro, but only rarely in vivo. Herein we report results of replicate experimentally evolved populations of Streptococcus pneumoniae propagated by repeated murine nasal colonization with the aim of identifying gene products under strong selection as well as the population genetic dynamics of infection cycles. Frameshift mutations in one gene, dltB, responsible for incorporation of d-alanine into teichoic acids on the bacterial surface, evolved repeatedly and swept to high frequency. Targeted deletions of dltB produced a fitness advantage during initial nasal colonization coupled with a corresponding fitness disadvantage in the lungs during pulmonary infection. The underlying mechanism behind the fitness trade-off between these two niches was found to be enhanced adherence to respiratory cells balanced by increased sensitivity to host-derived antimicrobial peptides, a finding recapitulated in the murine model. Additional mutations that are predicted to affect trace metal transport, central metabolism, and regulation of biofilm production and competence were also selected. These data indicate that experimental evolution can be applied to murine models of pathogenesis to gain insight into organism-specific tissue tropisms. IMPORTANCE Evolution is a powerful force that can be experimentally harnessed to gain insight into how populations evolve in response to selective pressures. Herein we tested the applicability of experimental evolutionary approaches to gain insight into how the major human pathogen Streptococcus pneumoniae responds to repeated colonization events using a murine model. These studies revealed the population dynamics of repeated colonization events and demonstrated that in vivo experimental evolution resulted in highly reproducible trajectories that reflect the environmental niche encountered during nasal colonization. Mutations impacting the surface charge of the bacteria were repeatedly selected during colonization and provided a fitness benefit in this niche that was counterbalanced by a corresponding fitness defect during lung infection. These data indicate that experimental evolution can be applied to models of pathogenesis to gain insight into organism-specific tissue tropisms.

scholarly journals Ceftazidime-Avibactam Resistance Associated with Increased blaKPC-3 Gene Copy Number Mediated by pKpQIL Plasmid Derivatives in Sequence Type 258 Klebsiella pneumoniae

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Marco Coppi ◽  
Vincenzo Di Pilato ◽  
Francesco Monaco ◽  
Tommaso Giani ◽  
Pier Giulio Conaldi ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Copy Number ◽  
Acquired Resistance ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Content Type ◽  
Outer Membrane Porins ◽  
Long Read ◽  
Multiple Copies

ABSTRACT This study reports on the characterization of two ceftazidime-avibactam (CZA)-resistant KPC-producing Klebsiella pneumoniae strains (KP-14159 and KP-8788) sequentially isolated from infections occurred in a patient never treated with CZA. Whole-genome sequencing characterization using a combined short- and long-read sequencing approach showed that both isolates belonged to the same ST258 strain, had altered outer membrane porins (a truncated OmpK35 and an Asp137Thr138 duplication in the L3 loop of OmpK36), and carried novel pKpQIL plasmid derivatives (pIT-14159 and pIT-8788, respectively) harboring two copies of the Tn4401a KPC-3-encoding transposon. Plasmid pIT-8788 was a cointegrate of pIT-14159 with a ColE replicon (that was also present in KP-14159) apparently evolved in vivo during infection. pIT-8788 was maintained at a higher copy number than pIT-14159 and, upon transfer to Escherichia coli DH10B, was able to increase the CZA MIC by 32-fold. The present findings provide novel insights about the mechanisms of acquired resistance to CZA, underscoring the role that the evolution of broadly disseminated pKpQIL plasmid derivatives may have in increasing the blaKPC gene copy number and KPC-3 expression in bacterial hosts. Although not self-transferable, similar elements, with multiple copies of Tn4401 and maintained at a high copy number, could mediate transferable CZA resistance upon mobilization.

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