The main objective of the MON4STRAT Project is to improve β-lactam-based antibiotic therapy of critically-ill patients for moving towards individualized treatments meeting efficacy as well as reduced EDR and adverse effects.
Thus, the Project aims to develop and demonstrate at the clinical level (by performing exploratory clinical trials), an innovative approach usable directly at the patient bed-side allowing the care-giver to correct and adapt its initial β-lactam treatment regimen (dosage, dose interval, and duration) to the patient-specific needs as soon as there is a quantitative evidence that the initial treatment is no longer appropriate and is likely to lead to poor clinical outcomes (lack of efficacy) as well as risks of EDR and/or adverse effects.
More particularly, for offering such evidence-based dosage adjustment perspectives, we aim at developing the approach of the Project (the MON4STRAT approach) by including the essential steps of:
- monitoring in quasi real-time (5 minutes) the free β-lactam blood levels at the patient bed-side at any time during the treatment,
- managing the deviation between such levels and efficacy targets (PK-PD) that will be optimized for minimizing EDR and adverse effects,
- correcting dosage and dose interval, accordingly, in order to maintain the plasma concentration of β-lactams above a pre-defined threshold while reducing/suppressing EDR and of adverse effects during the treatment.
To reach our main objective, we propose also to conduct two exploratory, open, randomized multicentre clinical trials involving critically-ill patients suffering from nosocomial pneumonia (HAP/VAP) : (i) one in adult patients (n=150) (ii) one in paediatric population (n=70).
In study #1 (adults), the objectives are
- at the level of the individual patient,
- to demonstrate that the application of the MON4STRAT approach will allow maintaining the free β-lactam blood levels at PK-PD targets optimized for leading to reduction of EDR and toxicity,
- to identify and assess a clear trend regarding improved cure rate/decrease mortality, shortening of treatment duration and avoidance of side effects.
- at the population level,
- to document how the MON4STRAT approach decreases and, if possible, prevents the emergence of low-level resistance, beyond what is observed at the individual level
- to demonstrate how this will address the situation of specific subpopulations (stratification) within the adult population (based on age, weight, severity of disease, underlying pathologies, alterations of excretory functions).
In study #2 (paediatric population), the objectives are
- at the level of the individual patient,
- to assess the ability to perform real-time monitoring taking into account the specific issues of this population (small amounts of blood; sparse sampling)
- to compare measured free β-lactam blood levels with those predicted from the best available population data
- at the population level,
- to document how the MON4STRAT approach could help to stratify this population into specific subpopulations (prematures, neonates, children) known to show major differences in drug pharmacokinetics.
Finally, throughout the whole Project duration, an important objective shared by all the partners is to pro-actively and strategically optimize the dissemination of the results to the best of the patients, the medical community and European companies collectively interested in fostering further developments including additional large-scale clinical trials to confirm the assets of the MON4STRAT approach and device.