Title: Minimising the risks of emergence of antibiotic resistance during therapy by precise regimen individualisation and use of combination therapy (MINIRES)
Funder: Department of Health and Social Care

Abstract: Background of the research Antimicrobial resistance is a major public health and healthcare problem. Resistance has severe implications for patients and communities. As there are few antimicrobials in development, optimal use of existing agents is vital. Intensive Care Units (ICU) provide an environment with high infection rates, high risks of emergence of resistance and are a focus for dissemination of resistance. There has been progressive development and utilisation of pharmacological modelling techniques to optimise patient care and an evolving understanding of the relationship between drug exposure and emergence of antibiotic resistance and clinical cure. Pre clinical models of antibiotic treatment have shown resistance occurs at much higher drug exposures than is possible in man &ndash; the implication being even high doses of a single drug may not be sufficient to minimise resistance. However, pre clinically, addition of a second drug has a dramatic reduction in risk of emergence of resistance. The impact of combination antimicrobial therapy on risk of emergence of resistance in man has never been studied and the use of modern pharmacokinetic software to individualise antibiotic dosing to minimise emergence of resistance is also novel. Aims of research The aim is to investigate the feasibility of conductinging a randomised trial to determine whether antibiotic regimen individualisation and combination therapy will reduce the risk of bacterial resistance. This hypothesis will be tested in intubated critically ill patients with Gram negative pulmonary infection. Plan of investigation Determine the impact of antibiotic regimen individualisation performed on days 2 and 4 of antibacterial therapy in addition to combination antimicrobial treatment on emergence of resistance and clinical cure. This will be assessed by a factorial 2x2 design randomised control trial where the four arms are:- Arm A standard care (standard dose piperacillin-tazobactam alone) Arm B personalised (individually optimised) dosing of piperacillin-tazobactam alone based on measurement of serum concentrations and dose modification to meet a pre defined pharmacodynamic index target Arm C standard care (standard doses of piperacillin-tazobactam) in combination with gentamicin dose according to local guidelines Arm D personalised (individually optimised) dosing of piperacillin-tazobactam as for Arm B and also gentamicin in combination, dosed to meet a pre determined pharmacodynamic index target Only patients with culture proven clinically diagnosed Gram negative pulmonary infection will be included. Piperacillin tazobactam will be measured in real time by LC/MS and subsequently dose adjustments made using a non parametric population pharmacokinetic modelling. Antimicrobial resistance will be established using standard methodologies and strains will be typed and the mechanism of resistance established. We will recruit 20 patients into each arm and collect data on a range of clinically relevant therapeutic outcome measures as well as the minimisation of resistance. It is expected patients may receive larger doses of antibiotic than in standard practice so adverse events will be tracked carefully. The objectives of the trial are assessing the feasibility of recruiting patients with Gram negative infection, evaluating if individualisation can be achieved in real-time, determining protocol compliance, provision of estimates of sample sizes for a definitive study, investigating retention and reasons for drop outs, estimating costs and testing data collection systems. Summary of benefits to patients and NHS This research meets the requirements of DH guidance on antibiotic stewardship: providing a mechanism to ensure the right dose is given at the right time. It also ensures the sustained effectiveness of older agents for the future by individualisation and combination. We will help provide proof of principle for individualisation and combination therapy as a way to minimise resistance &ndash; opening the way for similar approaches in other infections.

Lay abstract: Resistance to antimicrobial drugs (antibiotics) has been identified in the UK and many other countries as an important problem which, if not addressed, will have a major effect on how patients will be looked after in the future. One way to address the problem is to make sure that when patients need antibiotics they are given in large enough doses and with other antibiotics to make sure the bacteria being treated do not develop resistance to the antibiotics given. Patients who need to be cared for on Intensive Care Units (ICU) have a greater chance of becoming infected during their hospital stay than patients who spend no time in ICU and chest infections are one of the commonest infections they get. In the last 10 years new knowledge from research in laboratories and patients has made doctors question the way antibiotics are currently given and whether giving two drugs may be better than one. This proposed research will test how best to give antibiotics to inpatients who have chest infections being cared for in ICU. There are several parts to the proposal. First we will assess if measuring antibiotic concentrations in patients and then changing their drug doses to make sure enough drug is given will change the number of patients contracting resistant bacteria or responding to antibiotics. Second, we will test whether two antibiotics, rather than one, will reduce whether bacteria become resistant and/or improve clinical cures. To see if we will need a larger study in the future, we will collect a range of information necessary to plan such a study in a careful and clinically useful way.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION