Expected progress 1: b-lactam blood level monitoring opens the way to b-lactam TDM
Progress will be a comprehensive and unique solution to the current analytical difficulty in implementing b-lactam TDM in severely ill patients by providing an instrument that will:
- be operational at the “bed-side” and be usable by non-specialized personnel to obtain a fast result that will allow immediate reaction of the attending health care professionals; at the same time, the instrument acquisition and operating cost will be low, which makes the approach affordable by almost any health care centre dealing with severely-ill patients. Operating directly at bed-side solves also most of the problems related to degradation of the b-lactams during samples storage and handling,
- rely on a highly a specific method of detection (specific enzymatic recognition of the b-lactam ring) that should mitigate the problems of interference,
- detect the free fraction only, which solves the problem of variability of protein-binding whatever the b-lactam used or the situation of the patient.
Expected progress 2: a new software for running b-lactam TDM based on the proper management of experimental b-lactam blood levels and optimized PK-PD targets
The approach for performing the translation of actual blood levels, as measured by the MON4STRAT device, into a dosage adjustment recommendation is certainly a key progress in the field of b-lactam dosage strategies. The MON4STRAT approach will bring a decision tool for proposing dosage correction recommendations which will not only rely on the access, for the first time, to real-time free b-lactam concentrations (expected progress 1) but also on improved PK-PD targets (expected progress 2).
Improved PK-PD targets means that:
- instead of using population-based PK-PD drug exposures of existing libraries, in-house libraries will be available enriched with data generated by previous studies performed by the applicants as well as those collected in the clinical study of this Project.
- PK-PD targets and models usable for the b-lactams of this Project (piperacillin-tazobactam, ceftazidime, cefepime, imipenem-cilastatin, meropenem) will be refined and confirmed,
- the PK-PD targets will be optimized for leading not only to improved efficacy but also to mitigation of EDR and adverse effects.
The resulting decision-making tool will be implemented into a software that will complete the MON4STRAT device which will be user-friendly, deliver results in a clear manner and in short periods of time after sampling. The combination of the dosage device with the decision-making algorithm is new and does not yet exist for b-lactam TDM.
Expected progress 3: proof-of concept (translational) studies to establish that optimized PK-PD targets leads to mitigation of EDR
Better knowledge will be generated, at the level of in vitro static and dynamic studies, on how emergence of low-level resistance can be suppressed by manipulating the concentration of b-lactams (in terms of multiples of MIC) and the time during which this concentration must be maintained to avoid the emergence of resistance. When brought to the clinics and translated into usable dosage recommendations, this should contribute to a reduction of low-level EDR during treatment.
Thus, progress will be brought by the translational nature of the approach (bench to bed-side to bench) with respect to minimization of EDR. By confronting actual blood level values with (i) optimized PK-PD targets leading to suppression of EDR, (ii) potential MIC drifts and (iii) data on subpopulations with decreased susceptibility, MON4STRAT will provide the clinician with a knowledge-based means to manage the trade-off between efficacy and the assessed EDR at the level of the individual patient.
This is an essential progress since it should not be achievable without actual blood levels data.
Expected progress 4: correlation between toxicity and b-lactam blood levels
Until now, no specific attempt has been performed for optimizing the b-lactam dosages while monitoring and controlling toxic effects. This is because of the limited access to direct information on the actual blood levels in patients experiencing adverse effects. Progress will be brought by establishing direct correlations between actual free b-lactam blood levels (used as surrogate/predictive value for the actual level in the cerebrospinal fluid) and recording of toxicity events (including, in at least one centre, EEG recordings during treatment).
Expected progress 5: individualized treatment based on patient-specific dosage corrections will be possible
Altogether the expected progresses 1 to 4 will lead to the MON4STRAT approach which is the main progress of this Project by filling the gap of still unsatisfactory means for b-lactam dosage corrections in critically-ill patients such as HAP/VAP patients.
The MON4STRAT approach, if successful, will allow to individualize a b-lactam dosage regimen. The essential parameter in the approach is the b-lactam free blood levels regularly monitored during the treatment. The deviation of the experimental blood levels and the population-based PK-PD targets will be a signature of the patient situation. Rapid corrective actions will be possible, if needed, at the very early stage of the treatment. In other cases, where only minor deviations are observed, dose adjustment will not be needed. This method enables to tailor the dosage to the actual and specific needs of the patient according to its particular situation, previous history, illness or resistance profile.
Expected progress 6: a set of statistically relevant clinical data for starting HAP/VAP stratification into subpopulations
The application of the MON4STRAT approach within the experimental arm of a randomized clinical trial involving 150 HAP/VAP patients will generate, after data management, a set of reconciled data completed with a statistical analysis. Based on the statistically relevant results, one expects to gain knowledge on how the HAP/VAP population can be stratified in subpopulations according to common traits and reactions experienced by individual patients. One may expect to gain information on how far the stratification is observed, namely in terms of the number of subpopulations. At this stage, it seems too early to anticipate whether or not clear sub-populations will come out of the results. It is the consortium’s opinion that broader clinical studies will be needed after the end of the project to deepen this issue.
Expected progress 7: an approach that can be used in paediatric populations
Paediatric populations are also at need of treatment optimization with b-lactams because of their rapidly changing pharmacokinetic parameters (related to the maturation of their excretory organs, when moving from the status of premature to that of neonate and older children) and relative immunodeficiency. The blood sample volumes needed for performing a MON4STRAT assay are small, which is definitely an advantage for monitoring paediatric patients. Information on free b-lactam blood levels in young patients is largely new and will pave the route to stratification and individualized treatments.