Author(s): John James Stewart Cadwell
Emerging antibiotic resistance presents a serious global health threat. Two million people in the United States were infected with antibiotic resistant bacteria in 2014 and more than 20,000 died as a direct result of these infections, many more from complications. Antimicrobial resistance has been identified as one of the three greatest threats to human health. Antibiotic discovery and development require static susceptibility testing to screen compounds, in vitro pharmacodynamics/ pharmacokinetic (PK/PD) studies to model drug dynamics and efficacy, and testing in animal models to provide critical information prior to the clinical evaluation of new antibiotics. The one compartment PK/PD model typically consists of an open central reservoir containing the organism of interest, a source of diluent and a waste reservoir. The disadvantage of this system includes: 1) Open system, not bio safe; 2) Bacteria numbers change over time; 3) Large volume requires large amount of drug and diluent; 4) Rapid changes in drug concentration not possible and cannot model short half-lives. Animal models have many shortcomings though they have served as a primary development tool for many years: It includes: 1) PK/ PD may not match human values; 2) Cannot sample same animal over time; 3)Difficult to study large numbers of bacteria to reveal resistance; 4) Many infections cannot be modeled in a mouse or other animal. To address these shortcomings, the two-compartment in vitro pharmacokinetic model utilizing hollow fiber bioreactors was developed, the Hollow fiber infection model (HFIM). The advantages of the HFIM are as follows: 1) Closed, bio-safe system; 2) Large number of organism can be tested, revealing resistance; 3) Precisely simulates human PK/PD; 4) Repetitive sampling over time, both drug and organism; 5) Total kill can be determined; 6) Single use, disposable, reproducible; 7) Two drug models can be tested; 8) Can model both dosing curve and elimination curve; 9) Can look at bacteria in different growth phases and in combination with cells. The clinical utility of the HFIM has been demonstrated and is now endorsed by the EMA. An overview of historic PK/PD models is presented and the utility of the system as it relates to antibiotics and other drugs are discussed.
The empty fiber contamination model speaks to a financially savvy pathway for quicker advancement of sheltered and viable dosing regimens, both for existing under-abused anti-toxins, or blends, and for new anti-microbials as a feature of an administrative accommodation process. EMA Workshop Non-Clinical Models to Identify PK/PD Indices and PD Targets In Vitro
The utilization of pre-cleaned, twofold packed away FiberCell polysulfone C2011, or cellulosic C3008 empty fiber cartridge modules, is generally revealed for this application. Accurately imitate any human fixation time profile for your antimicrobial medication competitor or lead compound Perfect for testing short half-life medication and mixes Take different examples after some time Study the development of obstruction over expanded periods, months if fundamental Assess all out slaughter Co-develop diverse cell types, for example mammalian cells, microscopic organisms, infections Rank new antimicrobial mixes by first testing a scope of half-lives/introduction times in vitro
Supplement stock with test drugs is quickly circled at 60 ml for every moment utilizing the Duet Pump through the permeable walled empty filaments (3 strands just are appeared here for straightforwardness). At this high stream rate sedate focuses will equilibrate all through the total circle including repository, extracapillary "PD compartment", and the luminal "PK compartment".
Medication presentation of the cells in the extracapillary compartment is exactly constrained by diluent expansion and waste evacuation likewise with the great chemostat single compartment model.
Diluent and waste repositories are kept outside the hatchery.
FiberCell Duet Pumps keep up high steady stream rates keeping the fixation in the focal supply equilibrated with that of the extra-slim space.
Low stream rate small scale processor controlled peristaltic siphons include and expel diluent from the focal supply inside the hatchery.
Testing by means of the side ports on the empty fiber cartridge.
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