scholarly journals In Vivo Activity of Oritavancin in Animal Infection Models and Rationale for a New Dosing Regimen in Humans

2012 ◽  
Vol 54 (suppl 3) ◽  
pp. S220-S228 ◽  
Author(s):  
P. G. Ambrose ◽  
G. L. Drusano ◽  
W. A. Craig
Keyword(s):  
Dosing Regimen ◽  
Infection Models ◽  
Animal Infection

scholarly journals Analysis of Endothelial Adherence of Bartonella henselae and Acinetobacter baumannii Using a Dynamic HumanEx VivoInfection Model

2015 ◽  
Vol 84 (3) ◽  
pp. 711-722 ◽  
Author(s):  
Marko Weidensdorfer ◽  
Ju Ik Chae ◽  
Celestine Makobe ◽  
Julia Stahl ◽  
Beate Averhoff ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Pathogenic Bacteria ◽  
Ex Vivo ◽  
Bartonella Henselae ◽  
Dependent Manner ◽  
Content Type ◽  
Human Pathogenic Bacteria ◽  
Infection Models ◽  
Animal Infection

Bacterial adherence determines the virulence of many human-pathogenic bacteria. Experimental approaches elucidating this early infection event in greater detail have been performed using mainly methods of cellular microbiology. However,in vitroinfections of cell monolayers reflect thein vivosituation only partially, and animal infection models are not available for many human-pathogenic bacteria. Therefore,ex vivoinfection of human organs might represent an attractive method to overcome these limitations. We infected whole human umbilical cordsex vivowithBartonella henselaeorAcinetobacter baumanniiunder dynamic flow conditions mimicking thein vivoinfection situation of human endothelium. For this purpose, methods for quantifying endothelium-adherent wild-type and trimeric autotransporter adhesin (TAA)-deficient bacteria were set up. Data revealed that (i)A. baumanniibinds in a TAA-dependent manner to endothelial cells, (ii) this organ infection model led to highly reproducible adherence rates, and furthermore, (iii) this model allowed to dissect the biological function of TAAs in the natural course of human infections. These findings indicate that infection models usingex vivohuman tissue samples (“organ microbiology”) might be a valuable tool in analyzing bacterial pathogenicity with the capacity to replace animal infection models at least partially.

scholarly journals Practical Synthesis of Iboxamycin, a Potent Antibiotic Candidate, in Amounts Suitable for Studies in Animal Infection Models

2021 ◽  
Author(s):  
Jeremy Mason ◽  
Daniel W. Terwilliger ◽  
Aditya R. Pote ◽  
Andrew G. Myers
Keyword(s):  
Reduction Reaction ◽  
Murine Models ◽  
One Pot ◽  
Ring Fusion ◽  
Negishi Coupling ◽  
Synthetic Strategy ◽  
Infection Models ◽  
Animal Infection ◽  
Practical Synthesis

A gram-scale synthesis of iboxamycin, an antibiotic candidate bearing a fused bicyclic amino acid residue, is presented. A pivotal transformation in the route involves an intramolecular hydrosilylation–oxidation sequence to set the ring-fusion stereocenters of the bicyclic scaffold. Other notable features of the synthesis include a high-yielding, highly diastereoselective alkylation of a pseudoephenamine amide, a convergent sp<sup>3</sup>–sp<sup>2</sup> Negishi coupling, and a one-pot transacetalization–reduction reaction to form the target compound’s oxepane ring. Implementation of this synthetic strategy has provided ample quantities of iboxamycin to allow for its <i>in vivo</i> profiling in murine models of infection.

scholarly journals Evaluation of Possible Correlations between Antifungal Susceptibilities of Filamentous Fungi In Vitro and Antifungal Treatment Outcomes in Animal Infection Models

1998 ◽  
Vol 42 (2) ◽  
pp. 282-288 ◽  
Author(s):  
F. C. Odds ◽  
F. Van Gerven ◽  
A. Espinel-Ingroff ◽  
M. S. Bartlett ◽  
M. A. Ghannoum ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Filamentous Fungi ◽  
Guinea Pigs ◽  
Survival Times ◽  
Pseudallescheria Boydii ◽  
Infection Models ◽  
Animal Infection ◽  
Effective Doses

ABSTRACT Nine isolates of filamentous fungi previously tested in 11 different laboratories for their susceptibilities to amphotericin B and itraconazole in vitro were injected intravenously into mice and guinea pigs, and responses to treatment with both agents were studied. The experiments were done in a single laboratory. Mean survival times, the percentages of animals surviving 12 days after infection, and culture results for samples of deep organs obtained postmortem were used as markers of antifungal efficacy. Because of variations in organism pathogenicity, interpretable test systems in vivo could not be established for Fusarium spp. in mice or guinea pigs or forPseudallescheria boydii in mice, even with the use of immunosuppressive pretreatments. Among the infections that could be evaluated, some degree of response to the corresponding treatment in vivo was seen in animals infected with each of two Rhizopus arrhizus isolates susceptible to amphotericin B at <0.5 μg/ml and Aspergillus spp. isolates susceptible to itraconazole at <1.0 μg/ml. Conversely, no responses were apparent with infecting strains for which MICs were ≥2 μg/ml (amphotericin B) or ≥1 μg/ml (itraconazole). However, the limitations of the intravenous challenge systems studied mean that no firm conclusion relating MICs in vitro to the lowest effective doses in vivo could be drawn.

scholarly journals Practical Synthesis of Iboxamycin, a Potent Antibiotic Candidate, in Amounts Suitable for Studies in Animal Infection Models

2021 ◽  
Author(s):  
Jeremy Mason ◽  
Daniel W. Terwilliger ◽  
Aditya R. Pote ◽  
Andrew G. Myers
Keyword(s):  
Reduction Reaction ◽  
Murine Models ◽  
One Pot ◽  
Ring Fusion ◽  
Negishi Coupling ◽  
Synthetic Strategy ◽  
Infection Models ◽  
Animal Infection ◽  
Practical Synthesis

A gram-scale synthesis of iboxamycin, an antibiotic candidate bearing a fused bicyclic amino acid residue, is presented. A pivotal transformation in the route involves an intramolecular hydrosilylation–oxidation sequence to set the ring-fusion stereocenters of the bicyclic scaffold. Other notable features of the synthesis include a high-yielding, highly diastereoselective alkylation of a pseudoephenamine amide, a convergent sp<sup>3</sup>–sp<sup>2</sup> Negishi coupling, and a one-pot transacetalization–reduction reaction to form the target compound’s oxepane ring. Implementation of this synthetic strategy has provided ample quantities of iboxamycin to allow for its <i>in vivo</i> profiling in murine models of infection.

scholarly journals In Vivo Pharmacodynamics of Ceftobiprole against Multiple Bacterial Pathogens in Murine Thigh and Lung Infection Models

2008 ◽  
Vol 52 (10) ◽  
pp. 3492-3496 ◽  
Author(s):  
W. A. Craig ◽  
D. R. Andes
Keyword(s):  
Serum Levels ◽  
Lung Infection ◽  
Lung Model ◽  
Dose Fractionation ◽  
Time Curve ◽  
Gram Negative ◽  
Infection Models ◽  
Bactericidal Activities

ABSTRACT Ceftobiprole medocaril is the parenteral prodrug of ceftobiprole, a novel pyrrolidinone broad-spectrum cephalosporin with in vitro and in vivo bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP). We have used murine thigh and lung infection models in neutropenic and normal mice to characterize the in vivo pharmacokinetic (PK)-pharmacodynamic (PD) activities of ceftobiprole against multiple strains of S. aureus (including MRSA), S. pneumoniae (including PRSP), and gram-negative bacilli. Serum levels of ceftobiprole following the administration of multiple doses were determined by a microbiological assay. In vivo bactericidal activities and postantibiotic effects (PAEs) of ceftobiprole against MRSA and PRSP strains were determined from serial CFU/thigh values following single doses of ceftobiprole (40 and 160 mg/kg of body weight). Dose fractionation studies were used to determine which PK-PD index correlated best with activity. Magnitudes of the PK-PD indices were calculated from MICs and PK parameters. A sigmoid dose-response model was used to estimate the dose (mg/kg/24 h) required to achieve a static and 2-log10 kill effects over 24 h. PK results showed area under the concentration-time curve/dose values of 1.8 to 2.8 and half-lives of 0.29 to 0.51 h. MICs ranged from 0.015 to 2 μg/ml. Ceftobiprole demonstrated time-dependent killing; its in vivo PAEs varied from 3.8 h to 4.8 h for MRSA and from 0 to 0.8 h for PRSP. The time above MIC (T > MIC) correlated best with efficacy for both MRSA and PRSP. The T > MIC values required for the static doses were significantly longer (P < 0.001) for Enterobacteriaceae (36 to 45%) than for S. aureus (14 to 28%) and S. pneumoniae (15 to 22%). The drug showed activities in the lung model similar to those in the thigh model. The presence of neutrophils significantly enhanced the activity of ceftobiprole against S. pneumoniae but only slightly against Klebsiella pneumoniae. Based on its PD profile, ceftobiprole is a promising new β-lactam agent with activity against gram-negative and gram-positive organisms including MRSA and PRSP.

scholarly journals In Vitro and In Vivo Activities of DA-7867, a New Oxazolidinone, against Aerobic Gram-Positive Bacteria

2005 ◽  
Vol 49 (6) ◽  
pp. 2498-2500 ◽  
Author(s):  
Eun Jeong Yoon ◽  
Yeong Woo Jo ◽  
Sung Hak Choi ◽  
Tae Ho Lee ◽  
Jae Keol Rhee ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Gram Positive Bacteria ◽  
Vancomycin Resistant Enterococci ◽  
Infection Models ◽  
Vancomycin Resistant

ABSTRACT In vitro and in vivo activities of DA-7867 were assessed against methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae. All isolates were inhibited by DA-7867 at ≤0.78 μg/ml, a four-times-lower concentration than that of inhibition by linezolid. For murine infection models, DA-7867 also exhibited greater efficacy than linezolid against all isolates tested.

scholarly journals Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory

2018 ◽  
Vol 115 (46) ◽  
pp. E10898-E10906 ◽  
Author(s):  
Sophie Viaud ◽  
Jennifer S. Y. Ma ◽  
Ian R. Hardy ◽  
Eric N. Hampton ◽  
Brent Benish ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Rest Period ◽  
Cell System ◽  
Cellular Activity ◽  
Dosing Regimen ◽  
Car T Cells ◽  
Car T

Chimeric antigen receptor (CAR) T cells with a long-lived memory phenotype are correlated with durable, complete remissions in patients with leukemia. However, not all CAR T cell products form robust memory populations, and those that do can induce chronic B cell aplasia in patients. To address these challenges, we previously developed a switchable CAR (sCAR) T cell system that allows fully tunable, on/off control over engineered cellular activity. To further evaluate the platform, we generated and assessed different murine sCAR constructs to determine the factors that afford efficacy, persistence, and expansion of sCAR T cells in a competent immune system. We find that sCAR T cells undergo significant in vivo expansion, which is correlated with potent antitumor efficacy. Most importantly, we show that the switch dosing regimen not only allows control over B cell populations through iterative depletion and repopulation, but that the “rest” period between dosing cycles is the key for induction of memory and expansion of sCAR T cells. These findings introduce rest as a paradigm in enhancing memory and improving the efficacy and persistence of engineered T cell products.

scholarly journals Allele- and Tir-Independent Functions of Intimin in Diverse Animal Infection Models

2012 ◽  
Vol 3 ◽  
Author(s):  
Emily M. Mallick ◽  
Michael J. Brady ◽  
Steven A. Luperchio ◽  
Vijay K. Vanguri ◽  
Loranne Magoun ◽  
...  
Keyword(s):  
Infection Models ◽  
Independent Functions ◽  
Animal Infection

scholarly journals Identification and Characterization of the PutP Proline Permease That Contributes to In Vivo Survival ofStaphylococcus aureus in Animal Models

1998 ◽  
Vol 66 (2) ◽  
pp. 567-572 ◽  
Author(s):  
William R. Schwan ◽  
Silvija N. Coulter ◽  
Eva Y. W. Ng ◽  
Michael H. Langhorne ◽  
Heather D. Ritchie ◽  
...  
Keyword(s):  
Animal Models ◽  
Reading Frame ◽  
High Affinity ◽  
Wound Model ◽  
Infection Models ◽  
Uptake Assay ◽  
Entire Open Reading Frame ◽  
In Vivo Growth

ABSTRACT Staphylococcus aureus is an important pathogen of humans and other animals, causing bacteremia, abscesses, endocarditis, and other infectious syndromes. A signature-tagged mutagenesis (STM) system was adapted for use in studying the genes required for in vivo survival of S. aureus. An STM library was ultimately created in S. aureus RN6390, with Tn917 being used to create the transposon mutations. Pools of S. aureusRN6390 mutants were screened in mouse abscess, bacteremia, and wound infection models for growth attenuation after in vivo passage. One of the mutants that was identified displayed marked attenuation following large-pool screening in all three animal models, which was confirmed in bacteremia and endocarditis models of infection with a smaller pool of mutants. Sequence analysis of the entire open reading frame showed a 99% identity to the high-affinity proline permease (putP) gene characterized in another strain of S. aureus. In wound and murine abscess infection models, the putP mutant was approximately 10-fold more attenuated than was wild-type strain RN6390. Another S. aureus strain transduced with theputP mutation also displayed an attenuated phenotype after passage in the wound model. A [3H]proline uptake assay showed that less proline was specifically transported into theputP mutant than into strain RN6390. The reduced viability of the bacteria possessing the mutation in the S. aureushigh-affinity proline permease suggests that proline scavenging by the bacteria is important for in vivo growth and proliferation and that analogs of proline may serve as potential antistaphylococcal therapeutic agents.

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