Systematic Analysis of Hollow Fiber Model of Tuberculosis Experiments

ABSTRACT The objective of these studies was to evaluate the exposures of meropenem and vaborbactam that would produce antibacterial activity and prevent resistance development in carbapenem-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae strains when tested at an inoculum of 108 CFU/ml. Thirteen K. pneumoniae isolates, three Enterobacter cloacae isolates, and one Escherichia coli isolate were examined in an in vitro hollow-fiber model over 32 h. Simulated dosage regimens of 1 to 2 g of meropenem with 1 to 2 g of vaborbactam, with meropenem administered every 8 h by a 3-h infusion based on phase 1 or phase 3 patient pharmacokinetic data, were studied in the model. A dosage of 2 g of meropenem in combination with 2 g of vaborbactam was bactericidal against K. pneumoniae, E. cloacae, and E. coli strains, with meropenem-vaborbactam MICs of up to 8 mg/liter. When the vaborbactam exposure was adjusted to the levels observed in patients enrolled in phase 3 trials (24-h free AUC, ∼550 mg · h/liter, versus 320 mg · h/liter in the phase 1 studies), 2 g of meropenem with 2 g of vaborbactam was also bactericidal against strains with meropenem-vaborbactam MICs of 16 mg/liter. In addition, this level of vaborbactam also suppressed the development of resistance observed using phase 1 exposures. In this pharmacodynamic model, exposures similar to 2 g of meropenem in combination with 2 g of vaborbactam administered every 8 h by a 3-h infusion in phase 3 trials produced antibacterial activity and suppressed the development of resistance against carbapenem-resistant KPC-producing strains of Enterobacteriaceae.

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Abstract A014: Evaluation of the hollow fiber model as a highly predictive in vivo testing system for the selection of xenograft tumor models in cancer drug discovery

10.1158/1535-7163.targ-17-a014 ◽

2018 ◽

Cited By ~ 1

Author(s):

Annika Sinz ◽

Holger Weber ◽

Cynthia Obodozie

Keyword(s):

Drug Discovery ◽

Hollow Fiber ◽

Cancer Drug ◽

Testing System ◽

Xenograft Tumor ◽

Fiber Model ◽

Cancer Drug Discovery ◽

In Vivo Testing ◽

Selection Of

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Role of the dosR-dosS Two-Component Regulatory System in Mycobacterium tuberculosis Virulence in Three Animal Models

Infection and Immunity ◽

10.1128/iai.01117-08 ◽

2008 ◽

Vol 77 (3) ◽

pp. 1230-1237 ◽

Cited By ~ 98

Author(s):

Paul J. Converse ◽

Petros C. Karakousis ◽

Lee G. Klinkenberg ◽

Anup K. Kesavan ◽

Lan H. Ly ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Animal Models ◽

Hollow Fiber ◽

Regulatory System ◽

Growth Defect ◽

Bacterial Survival ◽

Wild Type ◽

Fiber Model

ABSTRACT The Mycobacterium tuberculosis dosR gene (Rv3133c) is part of an operon, Rv3134c-Rv3132c, and encodes a response regulator that has been shown to be upregulated by hypoxia and other in vitro stress conditions and may be important for bacterial survival within granulomatous lesions found in tuberculosis. DosR is activated in response to hypoxia and nitric oxide by DosS (Rv3132c) or DosT (Rv2027c). We compared the virulence levels of an M. tuberculosis dosR-dosS deletion mutant (ΔdosR-dosS [ΔdosR-S]), a dosR-complemented strain, and wild-type H37Rv in rabbits, guinea pigs, and mice infected by the aerosol route and in a mouse hollow-fiber model that may mimic in vivo granulomatous conditions. In the mouse and the guinea pig models, the ΔdosR-S mutant exhibited a growth defect. In the rabbit, the ΔdosR-S mutant did not replicate more than the wild type. In the hollow-fiber model, the mutant phenotype was not different from that of the wild-type strain. Our analyses reveal that the dosR and dosS genes are required for full virulence and that there may be differences in the patterns of attenuation of this mutant between the animal models studied.

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Pharmacokinetics/Pharmacodynamics of Vaborbactam, a Novel Beta-Lactamase Inhibitor, in Combination with Meropenem

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01659-18 ◽

2018 ◽

Vol 63 (1) ◽

Cited By ~ 16

Author(s):

David C. Griffith ◽

Mojgan Sabet ◽

Ziad Tarazi ◽

Olga Lomovskaya ◽

Michael N. Dudley

Keyword(s):

Hollow Fiber ◽

Infection Model ◽

Beta Lactamase ◽

Fiber Model ◽

Content Type ◽

Development Of Resistance ◽

Wide Range ◽

Tract Infections ◽

Lactamase Inhibitor

ABSTRACT Vaborbactam is a novel beta-lactamase inhibitor with activity against important beta-lactamases, in particular, serine carbapenemases, and is currently approved in combination with meropenem as Vabomere for the treatment of complicated urinary tract infections, including pyelonephritis. This combination is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant Enterobacteriaceae. The objective of these studies was to evaluate vaborbactam pharmacokinetics (PK) and pharmacodynamics (PD) relationships for efficacy in a neutropenic mouse thigh infection model, as well as in an in vitro hollow-fiber infection model, in combination with a fixed exposure of meropenem using KPC-containing strains of Enterobacteriaceae. For both models, the meropenem dosage regimen was designed to simulate a 2-g dose administered every eight hours (q8h) by 3-h infusion. Vaborbactam dosage regimens were designed to produce a wide range of 24-h areas under the concentration-time curves (AUCs) in the thigh infection model. However, for the hollow-fiber model, the AUCs were limited to values of 192, 320, or 550 mg · h/liter. In both the animal and in vitro models, the PK-PD parameter that best described the antibacterial activity of vaborbactam, when administered in combination with meropenem at exposures equivalent to 2 g dosed q8h by 3-h infusion in humans, was the 24-h free vaborbactam AUC/meropenem-vaborbactam (with vaborbactam at 8 mg/liter) MIC ratio. The magnitude of this ratio for bacteriostasis was 9 to 12 and the magnitude to observe a 1-log kill was 18 to 38. In addition, a magnitude greater than 24 suppressed the development of resistance in the in vitro hollow-fiber model.

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A hollow fiber model for in vitro studies of cytotoxic compounds: activity of the cyanoguanidine CHS 828

Anti-Cancer Drugs ◽

10.1097/00001813-200101000-00005 ◽

2001 ◽

Vol 12 (1) ◽

pp. 33-42 ◽

Cited By ~ 17

Author(s):

Saadia B Hassan ◽

Manuel de la Torre ◽

Peter Nygren ◽

Mats O Karlsson ◽

Rolf Larsson ◽

...

Keyword(s):

Hollow Fiber ◽

In Vitro Studies ◽

Fiber Model ◽

Chs 828 ◽

Cytotoxic Compounds

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Correlations Between the Hollow Fiber Model of Tuberculosis and Therapeutic Events in Tuberculosis Patients: Learn and Confirm

Clinical Infectious Diseases ◽

10.1093/cid/civ426 ◽

2015 ◽

Vol 61 (suppl 1) ◽

pp. S18-S24 ◽

Cited By ~ 42

Author(s):

Tawanda Gumbo ◽

Jotam G. Pasipanodya ◽

Eric Nuermberger ◽

Klaus Romero ◽

Debra Hanna

Keyword(s):

Hollow Fiber ◽

Fiber Model ◽

Tuberculosis Patients

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A Long-term Co-perfused Disseminated Tuberculosis-3D Liver Hollow Fiber Model for Both Drug Efficacy and Hepatotoxicity in Babies

EBioMedicine ◽

10.1016/j.ebiom.2016.02.040 ◽

2016 ◽

Vol 6 ◽

pp. 126-138 ◽

Cited By ~ 28

Author(s):

Shashikant Srivastava ◽

Jotam G. Pasipanodya ◽

Geetha Ramachandran ◽

Devyani Deshpande ◽

Stephen Shuford ◽

...

Keyword(s):

Hollow Fiber ◽

Drug Efficacy ◽

Fiber Model ◽

Disseminated Tuberculosis

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Forecasting Accuracy of the Hollow Fiber Model of Tuberculosis for Clinical Therapeutic Outcomes

Clinical Infectious Diseases ◽

10.1093/cid/civ427 ◽

2015 ◽

Vol 61 (suppl 1) ◽

pp. S25-S31 ◽

Cited By ~ 54

Author(s):

Tawanda Gumbo ◽

Jotam G. Pasipanodya ◽

Klaus Romero ◽

Debra Hanna ◽

Eric Nuermberger

Keyword(s):

Hollow Fiber ◽

Forecasting Accuracy ◽

Fiber Model ◽

Therapeutic Outcomes

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Mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection

Scientific Reports ◽

10.1038/s41598-019-49556-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Frank Kloprogge ◽

Robert Hammond ◽

Karin Kipper ◽

Stephen H. Gillespie ◽

Oscar Della Pasqua

Keyword(s):

Steady State ◽

Hollow Fiber ◽

Lung Lesion ◽

Drug Combinations ◽

Target Tissue ◽

Fiber Model ◽

Pharmacokinetic Profiles ◽

Drug Concentrations

Abstract Here, we evaluate protocol requirements to mimic therapeutically relevant drug concentrations at the site of infection (i.e. lung lesion) in an in-vitro hollow fibre model of infection using pulmonary tuberculosis as a paradigm. Steady-state pharmacokinetic profiles in plasma, lung tissue and lung lesion homogenate were simulated for isoniazid, rifampicin and pyrazinamide and moxifloxacin. An R-shiny User Interface was developed to support conversion of in-vivo pharmacokinetic CMAX, TMAX and T1/2 estimates into pump settings. A monotherapy protocol mimicking isoniazid in lung lesion homogenate (isoniazid CMAX = 1,200 ng/ml, TMAX = 2.2 hr and T1/2 = 4.7 hr), and two combination therapy protocols including drugs with similar (isoniazid and rifampicin (CMAX = 400 ng/ml)) and different half-lives (isoniazid and pyrazinamide (CMAX = 28,900 ng/ml and T1/2 = 8.0 hr)) were implemented in a hollow-fiber system. Drug levels in the perfusate were analysed using ultra-high-performance liquid chromatographic-tandem mass spectrometric detection. Steady state pharmacokinetic profiles measured in the hollow fiber model were similar to the predicted in-vivo steady-state lung lesion homogenate pharmacokinetic profiles. The presented approach offers the possibility to use pharmacological data to study the effect of target tissue exposure for drug combinations. Integration with pharmacokinetics modelling principles through a web interface will provide access to a wider community interested in the evaluation of efficacy of anti-tubercular drugs.

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Effect of the Post-Spinning Solvent Exchange on the Performance of Asymmetric, Polyimide Hollow Fibers Prepared by Using a Triple-Orifice Spinneret

Materials ◽

10.3390/ma12213632 ◽

2019 ◽

Vol 12 (21) ◽

pp. 3632 ◽

Cited By ~ 2

Author(s):

Paola Bernardo ◽

Franco Tasselli ◽

Giovanni Chiappetta ◽

Gabriele Clarizia

Keyword(s):

Gas Separation ◽

Hollow Fiber ◽

Fiber Type ◽

Post Treatment ◽

Hollow Fibers ◽

Solvent Exchange ◽

Systematic Analysis ◽

Operation Conditions ◽

Gas Transport Properties ◽

Double Skin

Hollow fibers (HFs) are widely applied in different membrane operations, particularly in gas separation. The present work investigates the effect of post-spinning treatment on the gas transport properties of polyimide-based HFs. The membranes were spun by using both a conventional spinneret and a triple-orifice spinneret. A systematic analysis was carried out by considering different alcohols as the first fluid for the solvent exchange, with or without n–hexane as a second fluid. The HFs were characterized by exploring the change of the morphology and the permselective properties as a consequence of the operation conditions for spinning and post-treatments. According to the morphology, for a specific hollow fiber type, an optimal post–treatment was identified. The HFs prepared with the triple-orifice spinneret, using a solvent–rich shell fluid, can take advantage of the post-treatment using larger alcohols, while smaller alcohols should be preferred for the conventional spun HFs that present inside–outside double skin layers.

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