Evaluation of Ceftriaxone Plus Avibactam in an Intracellular Hollow Fiber Model of Tuberculosis: Implications for the Treatment of Disseminated and Meningeal Tuberculosis in Children

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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Systematic Analysis of Hollow Fiber Model of Tuberculosis Experiments

Clinical Infectious Diseases ◽

10.1093/cid/civ425 ◽

2015 ◽

Vol 61 (suppl 1) ◽

pp. S10-S17 ◽

Cited By ~ 41

Author(s):

Jotam G. Pasipanodya ◽

Eric Nuermberger ◽

Klaus Romero ◽

Debra Hanna ◽

Tawanda Gumbo

Keyword(s):

Hollow Fiber ◽

Systematic Analysis ◽

Fiber Model

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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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THE USE OF SERIAL HEMAGGLUTINATION TESTS IN FOLLOWING THE COURSE OF TUBERCULOSIS IN CHILDREN

PEDIATRICS ◽

10.1542/peds.14.4.340 ◽

1954 ◽

Vol 14 (4) ◽

pp. 340-345

Author(s):

VIRGINIA H. PEDEN ◽

KEITH E. VINCENT ◽

EDITH RICH

Keyword(s):

Prognostic Significance ◽

Spinal Fluid ◽

Older Children ◽

X Ray ◽

Hemagglutination Test ◽

Tuberculous Disease ◽

Absolute Height ◽

Tuberculin Testing ◽

Tuberculosis In Children ◽

Meningeal Tuberculosis

1. In cases of known pulmonary (or meningeal) tuberculosis in which X-ray (or spinal fluid) findings have become stabilized, a rise or fall in a previously stable hemagglutinin titer is a reliable indication that X-ray (or spinal fluid) evidence of improvement of the disease will follow within a few weeks. 2. A change in hemagglutinin titer occurring simultaneously with improvement in X-ray (or spinal fluid) findings serves as reliable additional evidence of improvement of the disease. 3. The significance of a changing hemaglutinin titer must always be evaluated with reference to X-ray (or spinal fluid) findings. A changing titer can be considered evidence of impending or beginning improvement of the disease only if the X-ray (or spinal fluid) findings are either static or improving. 4. A changing hemagglutinin titer was useful in predicting or confirming improvement of tuberculous disease in 38% of the group of cases studied. In the remaining cases, a change in hemagglutinin titer either failed to occur at all, or did not occur until after definite X-ray (or spinal fluid) improvement had taken place. 5. The absolute height of the hemagglutinin titer, in itself, was of no prognostic significance in connection with the course of tuberculosis in children. 6. In following the course of tuberculosis, the hemagglutination test is of more value in older children and in children with relatively mild forms of the disease than in infants or in patients with severe forms of tuberculosis, because the former are more likely to develop positive tests. 7. Tuberculin testing did not interfere with the use of the hemagglutination test in following the course of tuberculous disease.

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