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Research Themes

The Centre for Antimicrobial Pharmacodynamics (CAP) has five research themes that cover different therapeutic areas and patient groups, all centred around drug resistance and dose optimisation.

  • Development of New Antimicrobial Agents for Antimicrobial Resistance (AMR)

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    CAP collaborates with multiple companies and academics to develop new antimicrobial agents, especially to address AMR. CAP works in partnership with collaborators to provide pharmacodynamic data, PK/PD modelling, and strategic input into key drug development decisions. CAP can provide study design, bioanalysis and PK-PD modelling for lung penetration studies in collaboration with the Royal Liverpool Clinical Research Unit.

    Spero Therapeutics

    CAP is working with Spero Therapeutics on the development of SPR994 an oral carbapenem, and SPR206, which is a new polymyxin molecule.

    Allecra Therapeutics

    CAP is working with Allecra Therapeutics to develop preclinical and early phase clinical PK-PD packages for their extended spectrum ß-lactamase inhibitor AAI101, being developed in combination with cefepime. Some of this work is in collaboration with the Royal Liverpool Clinical Research Unit supported by the NIHR, where a Phase 1 clinical trial into lung epithelial lining fluid is being conducted.

    Antabio

    CAP is working with Antabio on the development of their metallo ß-lactamase inhibitor (MBLi) program. We are developing the preclinical PK-PD packages which will support dose selection for the early phase clinical program of a MBLi-carbapenem combination.

    AMR Centre

    The AMR centre is a UK R&D centre for antimicrobial resistance. CAP is partnered with the AMR centre to provide strategic, preclinical and clinical PK-PD support. The AMR centre works globally with companies and research institutions to support the development of new antimicrobial agents from lead optimization through to proof of concept and beyond.

    Medicinal Chemistry Programs for Cryptococcal Meningitis

    Lead is Dr Gemma Nixon with funding via an MRC New Investigator Award to develop new anti-cryptococcal compounds using a benzimidazole backbone.

    Nixon G, McEntee L, Johnson A, Farrington N, Whalley S, Livermore J, Natal C, Washbourn G, Bibby J, Berry N, Lestner J, Truong M, Owen A, Lalloo D, Hope W. 2018. Pharmacodynamics of flubendazole for cryptococcal meningoencephalitis: repurposing and reformulation of an anti-parasitic agent for a neglected fungal disease. Antimicrob Agents Chemother in press.

    F2G

    CAP worked with F2G on the preclinical and early phase clinical PK-PD of F901318, which is the lead candidate for a new class of antifungal agents. This work produced a several outputs described in the publications below, forms the basis for dose justification of this compound:

    Hope WW, McEntee L, Livermore J, Whalley S, Johnson A, Farrington N, Kolamunnage-Dona R, Schwartz J, Kennedy A, Law D, Birch M, Rex JH. 2017. Pharmacodynamics of the orotomides against Aspergillus fumigatus: New opportunities for treatment of multidrug-resistant fungal disease. MBio 8:e01157-17.

    Negri CE, Johnson A, McEntee L, Box H, Whalley S, Schwartz JA, Ramos-Martín V, Livermore J, Kolamunnage-Dona R, Colombo AL, Hope WW. 2017. Pharmacodynamics of the novel antifungal agent F901318 for acute sinopulmonary aspergillosis caused by Aspergillus flavus. J Infect Dis in press.

    Oliver JD, Sibley GEM, Beckmann N, Dobb KS, Slater MJ, McEntee L, du Pré S, Livermore J, Bromley MJ, Wiederhold NP, Hope WW, Kennedy AJ, Law D, Birch M. 2016. F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase. Proc Natl Acad Sci U S A 113:12809–14.

    AiCuris

    Partners the ND4BB/IMI consortium with AiCuris to develop new treatment options for multi-drug resistant Gram negative infections. Close collaboration with Professor Alasdair MacGowan, Professor Andy Lovering (North Bristol Trust), and Dr Richard Fitzgerald, Director of the Clinical Research Unit at the Royal Liverpool University Trust.

    Auspherix

    CAP has helped Auspherix develop new novel class of organogold-based antibiotics.

    Pneumonia

    Dr Sara Boyd is an MRC Clinical PhD Fellow funded by the North West England MRC Fellowship Scheme in collaboration with Roche to develop a better understanding of the penetration of meropenem into the lung using MALDI-MSI.

    Amplyx Pharmaceuticals

    Collaboration with Amplyx for the preclinical pharmacokinetics and pharmacodynamics of APX001, which is a first-in-class broad spectrum antifungal agent.

    Academic collaborations

    Dr Ishwar Singh, University of Lincoln for the developed of teixobactin analogues.

  • Better Use and Understanding of Existing Antibiotics

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    Fosfomycin

    Fosfomycin is emerging as a critical last-resort agent for the treatment of multidrug resistant bacterial infections in the NHS. See for example:

    • Merino, Vicente; Docobo-Perez, Fernando; Sojo-Dorado, Jesus; Morales, Isabel; Lupión, Carmen; Martín, Dolores; Cameán, Manuel; Hope, William; Pascual, Alvaro; Rodriguez-Baño, Jesús Population Pharmacokinetics and pharmacodynamics of fosfomycin in non-critically ill patients with bacteremic urinary infection caused by multidrug-resistant Escherichia coli, Clinical Microbiology and Infection, in press
    • Li G, Standing J, Bielicki J, Hope W, van den Anker J, Heath P, Sharland M. 2017. The potential role of fosfomycin in neonatal sepsis caused by multidrug-resistant bacteria. Drugs 77:941–50.
    • Sime FB, Johnson A, Whalley S, Santoyo-Castelazo A, Montgomery AB, Walters KA, Lipman J, Hope WW, Roberts JA. 2017. Pharmacodynamics of aerosolized fosfomycin and amikacin against resistant clinical isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae in a hollow fibre infection model: Experimental basis for combination therapy. Antimicrob Agents Chemother 61:e01763–16.
    • Docobo-Pérez F, Drusano GL, Johnson A, Goodwin J, Whalley S, Ramos-Martín V, Ballestero-Tellez M, Rodriguez-Martinez JM, Conejo MC, Van Guilder M, Rodríguez-Baño J, Pascual A, Hope WW. 2015. Pharmacodynamics of fosfomycin: Insights into clinical use for antimicrobial resistance. Antimicrob Agents Chemother 59:5602–5610.

    AIDA is an EU FP7-funded grant award to examine the potential use of old off-patent antibiotics against multi-resistant bacteria. The assessment of clinical efficacy by a pharmacokinetic/pharmacodynamic approach to optimise effectiveness and reduce resistance for off-patent antibiotics. We are helping with the preclinical and clinical PK-PD for the repurposing and optimisation of old antibiotics against MRSA.

    Glycopeptides

    NeoVanc is an EU FP7-funded programme examining the treatment of bacterial sepsis with vancomycin in neonates and infants aged under three months. Definition the PK-PD of vancomycin against coagulase negative staphylococci to help identify safe and effective regimens for further clinical study in neonates.

    We are also working on the PK-PD of teicoplanin against MRSA and have published the population PK of this agent in children in collaboration with the Clinical Research Facility at Alder Hey Hospital.

    Antifungal Agents

    Extensive work to define optimum use of voriconazole, isavuconazole, posaconazole, various formulations of amphotericin B, and the echinocandins.

  • Antimicrobials for Neglected and Tropical Infections

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    Cryptococcal Meningitis

    Katherine Stott is currently based in Blantyre in Malawi working on the AMBITION project and developing PK-PD models of cryptococcal meningitis.

    We have established collaborations with several clinical researchers to define the clinical PK-PD of antifungal agents for cryptococcal meningitis:

    1. Dr Joe Jarvis for the AMBITION trial; 
      Molefi M, Chofle AA, Molloy SF, Kalluvya S, Changalucha JM, Cainelli F, Leeme T, Lekwape N, Goldberg DW, Haverkamp M, others. 2015. AMBITION-cm: intermittent high dose AmBisome on a high dose fluconazole backbone for cryptococcal meningitis induction therapy in sub-Saharan Africa: study protocol for a randomized controlled trial. Trials 16:276.
    2. Professor Tom Harrison (St George's Hospital) and Dr Tihana Bicanic (St George's Hospital) and Dr Neil Stone (St George's Hospital) with funding from Wellcome Trust Strategic Award (WTSA) to for a Clinical PhD to better understand the pharmacodynamics of fluconazole for cryptococcal meningitis.
    3. Dr Jeremy Day and Dr Justin Beardsley (Oxford Clinical Trials Research Unit, Ho Chi Minh City, Vietnam) to define the PK-PD of amphotericin B deoxycholate and fluconazole for cryptococcal meningitis.
    4. Professor John Perfect, Duke University to define the PK-PD of isavuconazole for cryptococcal meningitis.

    Tuberculosis

    Dr Jodi Lestner has an MRC-funded Clinical Research Training Fellowship to study the spatial pharmacokinetics of anti-tuberculous agents with the central nervous system. Preclinical models will be used along with our newly acquired MALDI-MSI to define the penetration of drug into infected areas. Mathematical models will be developed to describe the way in which different drug distribute into CNS sub compartments.

    Schistosomiasis

    Collaboration with Dr Amaya Bustinduy (LSTHM) to better characterise the pharmacokinetics and pharmacodynamics of praziquantel in children.

    • Bustinduy AL, Waterhouse D, De Sousa-Figueiredo JC, Roberts SA, Atuhaire A, Van Dam GJ, Corstjens PLAM, Scott JT, Stanton MC, Kabatereine NB, Ward S, Hope WW, Russell Stothard J. 2016. Population pharmacokinetics and pharmacodynamics of praziquantel in Ugandan children with intestinal schistosomiasis: Higher dosages are required for maximal efficacy. MBio 7:e00227-16.

    And has an ongoing collaboration with Dr Bustinduy and Professor Jennifer Friedman (Brown University, USA) to define the PK of praziquantel in pregnancy.

    Taloramycosis

    Collaboration with Thuy Le to better understand the PK-PD of amphotericin B deoxycholate and itraconazole for taloramycosis.

  • Individualisation of Antimicrobial Therapy

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    Development, testing and implementation of software to enable individualisation of antimicrobial (antifungal and antibacterial) therapy for critically ill neonates, children and adults.

    This work has been funded by the National Institute for Health Research (NIHR) and the Medical Research Council (MRC). Software has been developed in collaboration with the Laboratory of Applied Pharmacokinetics  for the following drugs. 

    Voriconazole

    (PIVOTAL)

    Software for Dosage individualisation of Voriconazole for Immunocompromised Patients

    Neely M, Margol A, Fu X, Van Guilder M, Bayard D, Schumitzky A, Orbach R, Liu S, Louie S, Hope W. 2015. Achieving target voriconazole concentrations more accurately in children and adolescents. Antimicrob Agents Chemother 59:3090–3097.

    Piperacillin/ tazobactam

    Funded by an RfPB grant from NIHR for individualised therapy for piperacillin and gentamicin for critically ill ventilated patients with pneumonia in collaboration with Alasdair MacGowan and Dr Tim Felton.
    Felton TW, Roberts JA, Lodise TP, Van Guilder M, Boselli E, Neely MN, Hope WW. 2014. Individualization of piperacillin dosing for critically ill patients: Dosing software to optimize antimicrobial therapy. Antimicrob Agents Chemother 58:4094–4102.

    Teicoplanin

    Ramos-Martín V, Neely M, Padmore K, Peak M, Beresford MW, Turner M, Paulus S, Lopez-Herce J, Hope W. 2017. Tools for the individualized therapy of teicoplanin for neonates and children. Antimicrob Agents Chemother 61:e00707-17.

  • Pharmacokinetics and Pharmacodynamics in Special Populations

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    Neonatal Drug Development

    CAP is collaborating with Dr Danny Benjamin (Duke University) on and FDA funded award to better understand the development of new antibiotics for premature neonates.

    Neonatal and Paediatric Pharmacokinetics and Pharmacodynamics

    NeoVanc is an EU FP7-funded programme examining the treatment of bacterial sepsis with vancomycin in neonates and infants aged under three months. APT has recently published the PK-PD of vancomycin against coagulase negative staphylococci to help identify safe and effective regimens for further clinical study in neonates.

    Ramos-Martín V, Johnson A, Livermore J, McEntee L, Goodwin J, Whalley S, Docobo-Pérez F, Felton TW, Zhao W, Jacqz-Aigrain E, Sharland M, Turner MA, Hope WW. 2016. Pharmacodynamics of vancomycin for CoNS infection: experimental basis for optimal use of vancomycin in neonates. J Antimicrob Chemother 71:992–1002.

    PK-PD of teicoplanin against MRSA and has recently published the population PK of this agent in children in collaboration with the Clinical Research Facility at Alder Hey Hospital.

    Ramos-Martín V, Neely M, McGowan P, Siner S, Padmore K, Peak M, Beresford M, Turner M, Paulus S, Hope W. 2016. Population pharmacokinetics and pharmacodynamics of teicoplanin in neonates: making better use of C-reactive protein to deliver individualized therapy. J Antimicrob Chemother 71:3168–3178.

    Ramos-Martín V, Neely M, Padmore K, Peak M, Beresford MW, Turner M, Paulus S, Lopez-Herce J, Hope W. 2017. Tools for the individualized therapy of teicoplanin for neonates and children. Antimicrob Agents Chemother 61:e00707-17.

    Antifungal Therapy

    Multiple contributions to a better understanding of antifungal agents in neonates and children. See for example:

    Huurneman LJ, Neely M, Veringa A, Pérez FD, Ramos-Martin V, Tissing WJ, Alffenaar JWC, Hope W. 2016. Pharmacodynamics of voriconazole in children: Further steps along the path to true individualized therapy. Antimicrob Agents Chemother 60:2336–2342.

    Hope WW, Kaibara A, Roy M, Arrieta A, Azie N, Kovanda LL, Benjamin DK. 2015. Population pharmacokinetics of micafungin and its metabolites M1 and M5 in children and adolescents. Antimicrob Agents Chemother 59:905–913.