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  • Periodic Report Summary 2 - MON4STRAT (Therapeutic Beta-Lactam Monitoring for Stratified Treatment of hospital-acquired pneumonia, improved dose-dependent efficacy, decreased treatment duration, and prevention of emergence of resistance)

Periodic Report Summary 2 - MON4STRAT (Therapeutic Beta-Lactam Monitoring for Stratified Treatment of hospital-acquired pneumonia, improved dose-dependent efficacy, decreased treatment duration, and prevention of emergence of resistance)

Project Context and Objectives:
Antibacterial drugs are facing increasing limitations in terms of effectiveness due to emergence of high-level resistance and significant decrease in bacterial susceptibility (low level resistance). These expose the patients to a risk of sub-therapeutic dosages that explains treatment failures and further emergence of drug resistance (EDR). To mitigate these risks, clinicians tend to increase drug dosages and/or to combine antibiotics. Real-time Therapeutic Drug Monitoring (TDM) of the antimicrobials in individual patients allow fine-tuning drug regimens (dosages and schedules of administration) to meet patient-specific pharmacological requirements for activity (pharmacodynamics) while, decreasing the risk of emergence of drug resistance (EDR) and controlling toxicity (toxicodynamics).
This is of main concern in Hospital-Acquired Pneumonia [HAP] (including Ventilator-Associated Pneumonia [VAP]. β-lactams remain at the cornerstone of the current treatments in HAP/VAP patients. However, the underlying illnesses have a marked impact on β-lactam distribution properties and on patient's excretory function, which creates much variability in their pharmacokinetics and the corresponding blood levels. Thus within the specific HAP/VAP patients groups, there is a need for patient stratification and for individualized treatment with β-lactams.
Adjusting treatment dosages and schedules to the specific patient's conditions using pharmacokinetic models requires knowing both the drug volume of distribution (VD) and its total clearance. But those are markedly perturbed in severely ill patients and subject to rapid changes, which makes predictions based on population models imprecise.
β-lactam antibiotics show a "time-dependent pattern" of antibacterial efficacy. Thus, the time during which the free drug concentration (unbound fraction) of the drug remains above the MIC (Minimum Inhibitory Concentration) is the dominant PK/PD index associated with bacterial killing (fT>MIC). Although the MIC of the causative organism may not be known before 24-48 h after isolation, its value can be estimated by using local epidemiological data or by using the value of the EUCAST clinical susceptibility breakpoints for the corresponding antibiotic/bacteria combination to guide dosing. These efforts, however, are largely useless if the clinician does not have the correct information concerning the actual free blood levels of β-lactams, often unpredictable at the individual patient's level. Optimal dosing is also a key parameter concerning emergence of drug resistance (EDR) and prevention of adverse side effects.
Actually, what is still missing today for really implementing β-lactam TDM is the possibility for the clinicians to obtain a rapid assessment of drug levels.
In this context, ULG, UCL and WOW, 3 partners of this MON4STRAT Project, have developed a patented assay that allows the highly specific, quantitative, real-time measurement of non-protein bound (free) β-lactam concentration in blood samples.
The concept of the MON4STRAT Project is to develop a novel and more rational approach to the treatment of HAP/VAP patients that combines (i) the knowledge of the β-lactam blood levels acquired on a real-time basis for individual patients, with (ii) best-in-class PK-PD and EDR models gained from population studies and optimized for minimizing EDR and adverse effects. Rapid determination of actual β lactam blood levels is the key to the success of this approach.
To achieve its objectives, the MON4STRAT consortium brings together experts in complementary disciplines. Thus, biochemists and experimental pharmacologists (at the origin of the patented assay; ULg and UCL) and engineers (responsible for the construction and operation of the device; WOW) closely collaborate with PK-PD experts (UCL, UHOUS, EXPRIMO), antimicrobial resistance experts (UHOUS, SERMAS) and clinicians (ICAN, SERMAS, ULB, UTARTU, UDSL, UHOUS) to launch an integrated program.

Project Results:
1) Non-Clinical WPs
==> Development and validation of the MON4STRAT (M4S) β-lactam dosing methodology (WP4)
The M4S methods for dosing piperacillin-tazobactam, ceftazidime, and meropenem were fully validated. A new method was developed from scratch to dose meropenem in presence of other different β-lactams (coming from previous/concurrent treatments). All methods were cross-validated against the standard reference HPLC-MS-MS. A significant effort was devoted to transfer the validated M4S methodology from the commercial instrument that was utilised for the biochemical method development and validation, to the M4S device developed in this project.
==> Integration of the β-lactam dosing methodology within a β-lactam TDM approach (WP2, WP3, WP5)
An Expectation Maximization algorithm was developed. In the TDM context this algorithm predicts how blood level concentrations will evolve under future treatment, using the observed concentrations as a prior. The reliability of this algorithm is being assessed in the pre-test and amended accordingly, when needed.
An in vitro hollow-fiber infection model was used to evaluate the impact of different dosing exposures on the emergence of resistance. Results about drug exposures needed to suppress resistance development have been consistent when the PK/PD exposures were adjusted to the corresponding MIC of the pathogen except for piperacillin / tazobactam, where an alternative PK/PD approach is needed to determine the optimal PK/PD exposure.
==> To prepare the experimental monitoring devices ready to host PK-PD libraries, EDR libraries, access to eCRF and data base to be used at the clinical sites
A new instrument, including most of the functionalities required for the determination of antibiotic-concentration by non-specialized staff was built from scratch. This instrument differs functionally from the commercial device. Two prototypes were installed in P4 and P7 centers, staff was trained and a pre-test (defined elsewhere) started at the end of 2015. The pre-test highlighted several weakness of the device, resulting in inaccurate results. The pre-test was suspended until a reliable version of the device was available. Last January, with an improved version 3 of the device, pre-test resumed.

2) Clinical WPs:
• To set the best protocol for using MON4STRAT method at bed-side in the actual conditions of ICUs (WP6, WP7, WP8)
Since no studies have been done before on value of TDM for PK endpoint in ICU settings, a clinical pre-study, including 50 patients, was implemented. This pre-study is considered as a pre-requisite for the MON4STRAT clinical trial and an important validation step to achieve. The pre-study aims to: (i) ensure the point of care’s feasibility of the MON4STRAT algorithm implementation and (ii) verify the accuracy of the device for determining free-meropenem concentrations. The design of the CRF, construction of DB and the clinical protocol for the pre-study were achieved. The pre-test started end October 2015, but because of device failures, it was suspended and resumed in January 2017, when a new improved version of the device was made available. The pre-test is expected to finish around May 2017, after that the adults trial will start. A study protocol to perform the pharmacokinetic study in newborns and children to assess the potential use of the MON4STRAT device in non-adult patients have been designed, as well as the respective CRF and ICF.

3) Transversal WPs:
• Draft down the required document to obtain authorisations from ethical committees to perform the trials
A protocol for collection, and use of blood samples from hospitalized patients (ICU) obtained as left-over from samples needed for Mon4strat method’s validation, have been written, submitted and accepted by the Ethical committee. For the pre-study, considering that two different countries were implicated, two different approaches have been followed to obtain authorisations.

Potential Impact:
The main outcome of the MON4STRAT Project is a new clinically validated approach for monitoring the treatment of HAP/VAP patients which integrates a rapid, simple and cost-effective device for monitoring free β-lactam blood levels performed at the patient’s bed-side and, accordingly, offers to the clinician, for the first time, (i) rapid indications on the possible patient-specific deviation of the point-of-care β-lactam blood levels compared to the theoretical PK/PD targets and, accordingly, (ii) rapid dosage adjustement/corrective means.
Accordingly, the MON4STRAT approach is expected:
• to impact the way β-lactams will be prescribed, used and administrated at the individual level in case of critically ill patients in hospitals such as HAP/VAP,
• due to its generic nature, to be (i) replicable for the treatment of HAP/VAP patients in other hospital settings outside the consortium and (ii) applicable to other infectious conditions, and other antimicrobials provided suitable adaptation of the detection technology is performed (after the end of the MON4STRAT Project).
The approach integrates the essential concerns that drive a better use of antimicrobials ie. optimizing the primary efficacy outcome while limiting the emergence of drug resistance (EDR) and adverse side-effects.
Key Performance Indicators that will be used to measure the impact at the end of the Project
• Number of patients with improved outcomes as a result of a dosage/duration correction decided on the basis of the application of the MON4STRAT approach
• Number of cases where the application of MON4STRAT leads to the reduction of EDR and adverse effects
• Number of care-givers involved in the clinical trial ready to adopt the approach beyond the trial
Beyond improving the use of already approved β-lactams, the MON4STRAT approach will broadly impact the field of therapeutic antimicrobial monitoring by customizing the monitoring method to antimicrobials other than the β-lactams used in this project (other β-lactams, other antibiotics for which no fast assay method is yet available [fluoroquinolones, e.g.], antifungals, alone or in combination) and, consequently, accelerate the appropriate dosage testing of new antimicrobial drug candidates, for which market authorization is sought. The urgent need to feed the new antimicrobial drugs pipeline is definitely a further opportunity for wide implementation of the MON4STRAT monitoring approach.
Broad implementation of the MON4STRAT approach relies also on the replication of device enabling rapid (real-time), accurate free β-lactam blood level monitoring. This means that all the steps towards its industrialization are foreseen during the Project duration. To this end, the consortium involves a Belgian SME (WOW technology) of engineers specialized in translating concepts (here β-lactam dosage concept and method) into user-friendly tools completed with the needed software for data treatment (feedback correction loop).
One may thus expect a rapid and widespread valorization of the acquired knowledge and expertise in the field of human health as well as animal health. These fields of R&D&I are part of the European Innovation Partnerships (EIP) initiatives underpinning the EU Framework for Research and Innovation (Horizon 2020).

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