The Hollow Fibre Infection Model (HFIM) for Antimicrobial PK/PD

The two-compartment hollow fibre infection model represents a cost effective pathway for faster development of safe and efficacious dosing regimens, both for existing under-exploited antibiotics, or combinations, and for new antibiotics as part of a regulatory submission process. EMA Workshop Non-Clinical Models to Identify PK/PD Indices and PD Targets In Vitro

The use of the hollow fibre two-compartment infection model (HFIM), using either polysulfone or cellulosic HF cartridges, is widely reported, see : [references]

  • Precisely mimic any human concentration-time profile for your antimicrobial drug candidate or lead compound
  • Take multiple samples over time from same system
  • Sample from distinct PK and PD compartments (intraluminal, extracapillary)
  • Evaluate total kill
  • Study the emergence of resistance over extended periods, months if necessary
  • Test various combination regimens
  • Evaluate different dosing regimens
  • Co-cultivate different cell types, e.g. bacteria and mammalian cells
  • Optimize and de-risk clinical trials
  • Rank new antimicrobial compounds by testing a range of half-lives/exposure times in vitro

Hollow Fibre 2-compartment PK/PD system

Cross section through hollow fibre cartridge

Cross section through a hollow fibre cartridge.

Nutrient broth with test drugs is rapidly circulated through the hollow fibres (Three fibres only are shown here for simplicity. A real-life cross section would show hundreds of fibres).

Drug concentrations equilibrate between the extracapillary PD compartment and the PK luminal compartment and central reservoir.

The drug exposure of the cells in the PD compartment can be precisely controlled.

Endorsed by the EMA for PK/PD studies with Mtb.

“The Agency has published on 7 February 2015 a qualification opinion on the in-vitro hollow fiber system model of tuberculosis (TB) (EMA/CHMP/SAWP/47290/2015 Corr.).

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Investigate the Emergence of Drug Resistance

The system is ideal for longer-term PK/PD studies to investigate the emergence of antimicrobial resistance, for example. It offers a level of precision and economy unattainable with animal models and bridges the gap between static assays, animal models and clinical trials

12 key advantages over
mouse thigh
model of infection

Single or 2-Drug Combination Systems

Single drug HFIM

Test organisms are retained in the hollow fiber cartridge.

Nutrient broth from the central reservoir is continuously re-circulated.

Drug is added to the central reservoir and elimination kinetics are controlled by adding diluent to the central reservoir.

The volume in the central reservoir remains constant.

Two-drug combination HFIM

Example Set-Up for Testing Many Antimicrobial Compounds

Example hollow fibre infection model installation

Example laboratory set up for the hollow fibre infection model (4 pumps 8 cartridges)

  • Diluent and waste reservoirs are kept outside the incubator.
  • FiberCell Duet Pumps maintain high constant flow rates keeping the concentration in the central reservoir equilibrated with that of the extra-capillary space.
  • Low flow rate micro-processor controlled peristaltic pumps add and remove diluent from the central reservoir inside the incubator.
  • Sampling via the side ports on the hollow fiber cartridge.

Biosafety for drug resistant pathogenic or genetically modified agents

FiberCell® hollow fibre cartridges are fully disposable and provide biosafe containment for testing of drug resistant or genetically modified organisms.

References:

Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and blaNDM-5: Preparation for a Postantibiotic Era. Bulman Z.PP; mBio 8(4)2017 [open access]

In vitro pharmacodynamic evaluation of ceftolozane/tazobactam against β-lactamase-producing Escherichia coli in a hollow-fibre infection model Soon, R et al. International Journal of Antimicrobial Agents 2017 49(1)[open access]

From lead optimization to NDA approval for a new antimicrobial: Use of pre-clinical effect models and pharmacokinetic/pharmacodynamic mathematical modeling. Drusano G.L.; Bioorg Med Chem. 2016[abstract]

Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps: Deshpande, D. et al.; Clin Infect Dis. 2016, 63 (3)S80-87 [abstract]

Concentration-Dependent Synergy and Antagonism of Linezolid and Moxifloxacin in the Treatment of Childhood Tuberculosis: The Dynamic Duo: Deshpande, D. et al.; Clin Infect Dis. 2016, 63 (3): S88-S94.[open access]

A Faropenem, Linezolid, and Moxifloxacin Regimen for Both Drug-Susceptible and Multidrug-Resistant Tuberculosis in Children: FLAME Path on the Milky Way: Deshpande, D. et al.; Clin Infect Dis. 2016, 63(3): S95-S101.: S88-S94.[open access]

Thioridazine as Chemotherapy for Mycobacterium avium Complex Diseases: Deshpande, D. et al.; Antimicrob. Agents Chemother. 2016 60 (8) 4652-4658 [open access]

EMA Qualification opinion: In-vitro hollow fiber system model of tuberculosis (HSF-TB): EMA/CHMP/SAWP/47290/2015

Continuous culture of Cryptosporidium parvum using hollow fiber technology: Morada, M. et al.; Int J Parasitol. 2016 Jan;46(1):21-9 [related presentation PDF]

A long-term Co-perfused Disseminated Tuberculosis-3D Liver Hollow Fiber Model for Both Drug Efficacy and Hepatotoxicity in Babies: Srivastava, S. et al.; EBioMedicine 2016; 6:126-138 [open access]

Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy: Brown, A. et al.; mBio vol. 6 (6) [open access]

Strategic Regulatory Evaluation and Endorsement of the Hollow Fiber Tuberculosis System as a Novel Drug Development Tool: Romero, K., Clay, R. and Hanna, D.; Clinical Infectious Diseases 2015 61 (1): S5–9 [open access]

In Vitro Pharmacodynamics of Various Antibiotics in Combination against Extensively Drug-Resistant Klebsiella pneumoniae Lim, Tze-Peng et al.; Antimicrobial Agents and Chemother. 2015 59(5): 2515–2524.[open access]

Correlations Between the Hollow Fiber Model of Tuberculosis and Therapeutic Events in Tuberculosis Patients: Learn and Confirm: Gumbo, T.;2015 [open access]

The Hollow Fiber Infection Model: Principles and Practice: Cadwell, J.;J Adv Antibiotics and Antibodies 2015, 1(1) [open access]

Colistin and doripenem combinations against Pseudomonas aeruginosa: profiling the time course of synergistic killing and prevention of resistance:Ly,N.S. et al.; Journal of Antimicrobial Therapy 2015 70(5): 1434-1442 [open access]

Hollow Fiber System Model for Tuberculosis: The European Medicines Agency Experience: Cavaleri, M. and Manolis, E.; Clin Infect Dis. (2015) 61 (suppl 1): S1-S4.[open access]
The in vitro hollow fiber system model has been qualified by the European Medicines Agency as a methodology for use in support of selection and development of antituberculosis regimens. More data are expected to be generated in the future to further characterize its value.

Rapid Drug Tolerance and Dramatic Sterilizing Effect of Moxifloxacin Monotherapy in a Novel Hollow-Fiber Model of Intracellular Mycobacterium kansasii Disease: Srivastava, S. et al.; Antimicrob. Agents Chemother. 2015, 59(4) [open access]

Model System to Define Pharmacokinetic Requirements for Antimalarial Drug Efficacy: Bakshi R., Shapiro A. et al.; Science Translational Medicine 2013:Vol. 5, Issue 205 [open access]

Thioridazine Pharmacokinetic-Pharmacodynamic Parameters “Wobble” during Treatment of Tuberculosis: a Theoretical Basis for Shorter-Duration Curative Monotherapy with Congeners Musuka, S. et al.; Antimicrob. Agents Chemother. 2013 vol. 57 no. 12 5870-5877 [open access]

PK/PD models in antibacterial development: Velkov, T. et al.; Curr Opin Microbiol . 2013, 16(5) [open access]

Hollow-fiber pharmacodynamics studies and mathematical modeling to predict the efficacy of amoxicillin for anthrax postexposure prophylaxis in pregnant women and children. Louie, A et al.; Antimicrob Agents Chemother 2013; 57:5946–60. [open access]

Relationship between Ceftolozane-Tazobactam Exposure and Drug Resistance Amplification in a Hollow-Fiber Infection Model: VanScoy, B. et al.; Antimicrobial Agents and Chemotherapy 2013 p 4134 – 4138. [open access]

The Hollow Fiber Infection Model for Antimicrobial Pharmacodynamics and Pharmacokinetics: Cadwell, J.; Adv Pharmacoepidem Drug Safety 2012 [open access]

In Vitro Activity of MK-7655, a Novel Beta-Lactamase Inhibitor, in Combination With Imipenem Against Carbapenem-Resistant Gram-Negative Bacteria: Hirsch,E.B. et al.; Antimicrobial Agents and Chemotherapy 2012; 56(7): 3753–57 [open access]

Simulated Antibiotic Exposures in an In Vitro Hollow-Fiber Infection Model Influence Toxin Gene Expression and Production in Community-Associated Methicillin-Resistant Staphylococcus aureus Strain MW2: Pichereau, S. et al.; Antimicrob Agents Chemother. 2012 Jan; 56(1): 140–147. [open access]

Effect of Half-Life on the Pharmacodynamic Index of Zanamivir against Influenza Virus Delineated by a Mathematical Model: Brown, A. et al.; Antimicrob. Agents Chemother. 2011 55 (4) 1747-1753

Antiviral pharmacodynamics in hollow fibre Bioreactors: McSharry, J. et al.; Antiviral Chemistry & Chemotherapy 2011; 21:183–192 [open access]

Pharmacokinetic Mismatch Does Not Lead to Emergence of Isoniazid- or Rifampin-Resistant Mycobacterium tuberculosis but to Better Antimicrobial Effect: a New Paradigm for Antituberculosis Drug Scheduling: Srivastava, S. et al; Antimicrob. Agents Chemother. 2011 55 (11): 5085-5089 [open access]

Moxifloxacin Pharmacokinetics/Pharmacodynamics and Optimal Dose and Susceptibility Breakpoint Identification for Treatment of Disseminated Mycobacterium avium Infection :Deshpande,D. et al.;Antimicrob Agents Chemother. 2010 54(6): 2534–2539. [open access]

Optimizing the Culture of Plasmodium Falciparum in Hollow Fiber Bioreactors :Preechapornkul,P. et al.;Southeast Asian J Trop Med Public Health. 2010 41(4): 761–769 [open access]

Ethambutol Optimal Clinical Dose and Susceptibility Breakpoint Identification by Use of a Novel Pharmacokinetic-Pharmacodynamic Model of Disseminated Intracellular Mycobacterium avium: <>Deshpande, D. et al.; Antimicrob Agents Chemother. 2010 54(5): 1728–1733 [open access]

Prediction of the Pharmacodynamically Linked Variable of Oseltamivir Carboxylate for Influenza A Virus Using an In Vitro Hollow-Fiber Infection Model System. McSharry, J.; Antimicrob. Agents Chemother. 2009 53 (6) 2375-2381 open access]

Pharmacodynamics of Cidofovir for Vaccinia Virus Infection in an In Vitro Hollow-Fiber Infection Model System. McSharry, J.; Antimicrob. Agents Chemother. 2009 53(1) 129-135 [open access] – system diagram

Pharmacodynamic Characterization of gemcitabine cytotoxicity in an in vitro cell culture bioreactor system. Kirstein MN, Brundage RC, Moore MM, Williams BW, Hillman LA, et al. 2008 Cancer Chemother Pharmacol 61: 291-299.

Comparative Pharmacodynamics of Gentamicin against Staphylococcus aureus and Pseudomonas aeruginosa: Tam, V. et al; Antimicrob Agents Chemother. 2006 50(8): 2626–2631

Selection of a moxifloxacin dose that suppresses drug resistance in Mycobacterium tuberculosis, by use of an in vitro pharmacodynamic infection model and mathematical modeling. Gumbo, T. et al.; J Infect Dis. 2004 Nov 1;190(9):1642-51. [open access]

Starter kit for PK/PD – infection model

Cat.# Description Qty
P3202 FiberCell® Systems Duet 1
C2011 High Flux PS Cartridge 20 kd (3000 cm2 – 20 ml) 1
C3008 Cellulosic Low Flux Cartridge 10 kd (2000 cm2 – 12 ml) 1
A1006 38mm Reservoir Cap 2
A1007 PK/PD Reservoir Cap Assembly 1

Please contact us to discuss the full list of items needed to set up a system for PK/PD and the best choice of cartridge for testing your compound(s).

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