Bridging the preclinical/clinical gap for optimisation of efficacy and avoidance of resistance for fluoroquinolones, application to canine pyoderma

A 3 year full-time fully-funded VMD / DEFRA funded PhD Scholarship open to Home/EU applicants only based at the Royal Veterinary College.

Department: Clinical Science and Services

Deep pyoderma cases are therapeutically challenging in veterinary practice, due to; limited penetration of drugs into fibrotic infected skin, the chronicity of the condition and limited susceptibility of the organisms to many drug classes. Consequently, many clinicians use fluoroquinolones, which are licensed for deep canine pyoderma (enrofloxacin, marbofloxacin and pradofloxacin). Fluoroquinolones are critically important in human medicine and their veterinary use may induce co-selection of resistant bacteria of clinical relevance for human patients. We hypothesise that, due to differences in susceptibility and adaptive resistance between fluoroquinolones, the critical values (clinical breakpoint) for efficacy and avoidance of resistance must be defined on a drug-by-drug basis, using a combination of in vitro and in vivo techniques described below:

- First, we will determine the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and mutant prevention concentration (MPC) of licensed veterinary and human fluoroquinolones against historically banked clinical isolates from cases of canine pyoderma (S. aureus, S. pseudintermedius and E. coli).

- Second, we will carry out static in vitro time-kill assays. Isolates of S. aureus, S. pseudintermedius, and E. coli will be exposed to 0, 0.25, 0.5, 1, 2, 4 and 8 multiples of MIC of marbofloxacin, enrofloxacin and pradofloxacin. Pharmacokinetic / Pharmacodynamic (PK/PD) modelling will be performed to calculate drug efficacy and potency and to determine the optimal drug-exposure value for prediction of efficacy.

- Third, real canine plasma concentration-time profiles for marbofloxacin and pradofloxacin will be reproduced in a hollow fiber infection model. Our group has gained experience with this dynamic system in a previous DEFRA-funded project. Dose fractionation experiments will confirm whether high concentration or long exposure best predict efficacy and resistance emergence. Marbofloxacin-resistant S. pseudintermedius strains will be cultured in the presence of low and high doses of marbofloxacin and pradofloxacin for 5 days and PK/PD modelling carried out.

- Fourth, we will conduct a non-interventional clinical study to establishing the temporal dynamic of antimicrobial resistance in dogs receiving fluoroquinolones. We will recruit twenty dogs with pyoderma or skin wounds which, after identification and susceptibility testing, will be treated for up to 8 weeks with either marbofloxacin or pradofloxacin. In vitro time kill assays on isolated pathogens will be conducted in parallel and compared to in vivo outcome (efficacy and resistance). The effect of fluoroquinolones on gastrointestinal and skin bacteria (resistance emergence and susceptibility restoration) will be evaluated before, during treatment and 4 weeks after the final dose. Also monitored will be fluoroquinolone saliva concentration and density per skin surface unit during treatment.

- Finally, the pharmacokinetic data and MIC distribution (literature data) together with the relationship between exposure and dynamic of bacterial kill modelled above will be used to propose clinical breakpoints (highest MIC value considered “sensitive”) for fluoroquinolones in canine pyoderma.

Outcomes from this work will inform clinicians, regulators and drug companies on clinical cut-offs values for efficacy and minimisation resistance of currently approved fluoroquinolones. The findings will also provide insights to regulators on the combined use of static and dynamic studies to support the registration process.


Requirements
We are looking for highly motivated candidates with excellent interpersonal communication skills. Applicants should also have excellent problem solving skills and become capable of independent laboratory work.

Ideal candidates are veterinary or medical graduate, although exceptional graduates with BSc or MSc could be considered. Applicants should have a strong interest and prior training in microbiology, dermatology and /or pharmacology/modelling. EU applicants must demonstrate sufficient level of English, for further information see English Language Proficiency. Travel expenses for interview not covered.


The studentship will ideally commence late March 2019, and the candidate will be based in the Hawkshead Campus (Hatfield) but may have to travel to central London (Camden campus) occasionally.

If you are interested in applying for this position, please follow the link below. Please use your personal statement to demonstrate any previous skills or experience you have in using both qualitative and quantitative research methods.

Interviews will take place on the 19th March at RVC’s Hawkshead.

We welcome informal enquiries - these should be directed to Dr. Ludovic Pelligand [Email Address Removed].

If you have any questions about the application process please direct these to [Email Address Removed].